Brk inhibitory compound

ABSTRACT

The present invention relates to a compound represented by general formula (I) (wherein, all symbols represent the same meanings as the symbols set forth in the specification), a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug of any of these. Since the compound has a Brk inhibitory activity, the compound is useful as a drug ingredient for the prevention and/or treatment of Brk-related diseases such as cancer, for example.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Phase of International PatentApplication No. PCT/JP2016/068429, filed Jun. 21, 2016, which claimspriority to Japanese Patent Application No. 2015-124315, filed Jun. 22,2015, the entireties of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a Brk inhibitory compound representedby the following general formula (I):

(wherein, all the symbols have the same meanings as described below), asalt thereof, a solvate thereof an N-oxide thereof, or a prodrug of anyof these (hereinafter, referred to as the compound of the presentinvention), and a medicament comprising the same as an activeingredient.

BACKGROUND ART

Brk (Breast tumor kinase) is also referred to as PTK6 (protein tyrosinekinase 6), and is a non-receptor tyrosine kinase which belongs to FRK(Fyn-related kinase)/PTK6 family kinases which are tyrosine kinases. Brkis coded by 451 amino acids. Brk was identified from human normalmelanocytes in the first place, and immediately after that, Brk wasidentified in breast cancer. Brk is highly expressed in a lot of tumorsincluding breast cancer, ovarian cancer, colon cancer, pancreaticcancer, bladder cancer, esophageal cancer, gastric cancer,non-small-cell lung cancer, prostate cancer, oral squamous cell cancer,head and neck squamous cell cancer, melanoma, B-cell lymphoma, andT-cell lymphoma. In particular, Brk is a poor prognostic factor inbreast cancer, prostate cancer, nasopharyngeal cancer, andnon-small-cell lung cancer. In addition, it is thought that Brk playsimportant roles in tumorigenesis such as promotion of proliferation,migration, and invasion of cancer cells, and avoidance of cell death(see Non Patent Literatures 1 to 7).

Accordingly, it is thought that a compound which inhibits activation ofBrk is useful for treating various types of cancer.

On the other hand, it has been described in Patent Literature 1 that, acompound of the following general formula (A) or a pharmaceuticallyacceptable salt or a derivative thereof is used for treatment oramelioration of one or more symptoms of α-synuclein toxicity,ca-synuclein mediated diseases, or diseases in which α-synuclein fibrilsare a symptom or cause of the disease.

The general formula (A) is as follows:

(wherein:each X^(A) is independently N or CH;R^(1 A) and Z^(A) are each independently R^(5 A), C(O)R^(5 A) or thelike;R^(2 A) and R^(3 A) are each independently H, halo, R^(5 A), OR^(5 A),OC(O)R^(5 A) or the like;R^(4 A) is independently H, halo, NR^(5 A) R^(5 A), NR^(5 A) R^(6 A) orthe like; or optionally substituted alkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl; and each of R^(5 A) and R^(6 A) is independently H, oroptionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, or heterocyclyl (the definition ofgroups is partly extracted)).

In addition, it has been described in Patent Literature 2 a method oftreating a subject for a disorder characterized by impaired proteintrafficking, comprising administering to the subject an effective amountof a compound represented by general formula (B) or a pharmaceuticallyacceptable salt thereof, wherein the disorder is not a synucleinopathy.

The general formula (B) is as follows:

(wherein:each X^(B) is independently N, CH or C(C₁-C₄ alkyl);each X^(1 B) is independently N, NR^(3 B), CH or C(C₁-C₄ alkyl);R^(1 B) and Z^(B) are each independently R^(5 B), C(O)R^(5 B) or thelike; or, NR^(1 B) Z^(B), taken together, is N═CH—NR^(5 B) R^(5 B);R^(2 B) and R^(3 B) are each independently H, halo, R^(5 B) or the like;R^(4 B) is independently H, halo, NR^(5 B) R^(5 B), NR^(5 B) R^(6 B) orthe like;or optionally substituted alkyl, aryl, aralkyl, heteroaryl orheteroaralkyl;and each of R^(5 B) and R^(6 B) is independently H, or optionallysubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl or heterocyclyl (the definition of groups is partlyextracted)).

Further, it has been described in Patent Literature 3 that a compound ofthe following formula (C) or a tautomer or pharmaceutically acceptablesalt thereof is used for treating Syk and/or JAK related diseases suchas cardiac disease, inflammatory disease, immune-related disease, andcell proliferative disorder.

The general formula (C) is as follows:

a compound having:

([wherein,Y^(1 a C) is selected from the group consisting of N, CH and C;Z^(1 a C) is selected from the group consisting of a bond, —SO₂—, —CO—,and the like;R^(1 a C) is selected from the group consisting of: (a) H, (b) C₁₋₈alkyl that may be substituted with 1 to 3 substituents selected from thegroup consisting of amino, hydroxy, C₁₋₈ alkoxy and the like, (c) C₃₋₈cycloalkyl that may be substituted with 1 to 3 amino substituents, (d)aryl that may be substituted with 1 to 3 substituents selected from thegroup consisting of C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylamino and thelike, (e) heterocyclyl, halogen, cyano that may be substituted with 1 to3 substituents selected from the group consisting of: C₁₋₈ alkyl, oxoand the like, cyano C₁₋₆ alkylcarbonyl, aminocarbonyl and the like, and(f) heteroaryl that may be substituted with 1 to 3 substituents selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ alkylsulfonyl and thelike;R^(2 a C) is H or C₁₋₈ alkyl or the like;R^(3 a C) is H or C₁₋₈ alkyl or the like;R^(4 a C) is selected from the group consisting of: (a) aryl that may besubstituted with 1 to 3 substituents R^(4 c C), each of which isindependently selected from the group consisting of: C₁₋₈ alkoxy, amino,C₁₋₈ alkylcarbonyl and aminocarbonyl C₁₋₈ alkoxy, (b) heteroaryl,heterobicyclic C₁₋₈ alkyl, halo, hydroxyl that may be substituted with 1to 3 substituents R^(4 c C), each of which is independently selectedfrom the group consisting of: C₁₋₈ alkyl, halogen, hydroxyl, oxo C₁₋₈alkoxy and ═S, (c) heterocyclyl that may be substituted with 1 to 3substituents R^(4 c C), each of which is independently selected from thegroup consisting of: C₁₋₈ alkyl and oxo;R^(4 b C) is selected from the group consisting of: H, C₁₋₈ alkyl, C₁₋₈alkylcarbonyl, C₁₋₈ alkylcarbonylamino, C₁₋₈ alkylsulfonyl, C₁₋₈alkylsulfinyl, C₁₋₈ alkylthio, C₁₋₈ alkoxy, C₁₋₈ alkoxycarbonylamino,C₁₋₈ alkoxycarbonyl, amino, aminocarbonyl, aminosulfonyl, aminocarbonylC₁₋₈ alkoxy, amino C₁₋₈ alkylene, carboxy, C₃₋₈ cycloalkylcarbonylamino,C₃₋₈ cycloalkylcarbonyl, halo, hydroxy, oxo and heterocyclyl;when R^(4 b C) is heterocyclyl, it may be substituted with 1 to 3substituents R^(4 d C) independently selected from the group consistingof: C₁₋₈ alkyl, C₁₋₈ alkoxy, hydroxy, amino, halo, cyano, oxo and thelike;R^(5 a C) is selected from the group consisting of H, C₁₋₈ alkyl and thelike;R^(6 a C) is selected from the group consisting of H, C₁₋₈ alkyl and thelike;R^(7 a C) is selected from the group consisting of H, C₁₋₈ alkyl, C₃₋₈cycloalkyl, and aryl and the like, each of aryl and heteroaryl may besubstituted with halo, C₁₋₈ alkyl, C₁₋₈ alkoxy, cyano, amino, hydroxyl,heteroaryl; and the dashed line indicates a double bond or a singlebond] or a tautomer or a pharmaceutically acceptable salt thereof (thedefinition of groups is partly extracted)).

However, none of the Patent Literatures describe or suggest a compoundwhich is selective for Brk.

CITATIONS LISTS Patent Literatures

Patent Literature 1: WO 2007/126841 A

Patent Literature 2: WO 2009/062118 A

Patent Literature 3: WO 2009/131687 A

Non Patent Literatures

Non Patent Literature 1: Breast Cancer-Current and AlternativeTherapeutic Modalities, pages 413-434, 2011

Non Patent Literature 2: Biochimica et Biophysica Acta, Vol. 1806, pages66-73, 2010

Non Patent Literature 3: Cell Cycle, Vol. 8, pages 2728-2732, 2009

Non Patent Literature 4: Cancer Research, Vol. 73, pages 5810-5820, 2013

Non Patent Literature 5: Cancer Research, Vol. 73, pages 5426-5437, 2013

Non Patent Literature 6: OncoTargets and Therapy, Vol. 6, pages 183-188,2013

Non Patent Literature 7: Journal of Translational Medicine, Vol. 11, 59,2013

SUMMARY OF INVENTION Technical Problems

An object of the present invention is to find out a compound useful as apreventive and/or therapeutic agent for various cancer diseases bycreating a compound having an inhibitory activity on Brk.

Solutions to Problems

The present inventors have carried out intensive studies to find acompound having an inhibitory activity on Brk in order to achieve theabove-described object. As a result, the present inventors have foundthat a compound represented by general formula (I) described below hasBrk inhibitory action and high Brk selectivity as compared with otherkinases, and have completed the present invention.

In other words, the present invention relates to the followings:

[1] A compound represented by general formula (I):

(wherein:

represents

Ring 1 represents a 3- to 15-membered ring;R¹ represents a halogen, an oxo group, a hydroxyl group, a cyano group,NR⁴R⁵, a C1-4 alkyl group, or a C1-4 alkoxy group, said C1-4 alkyl groupor C1-4 alkoxy group may be substituted with a halogen;R⁴ and R⁵ each independently represent a hydrogen atom, a C1-4 alkylgroup, or a C1-4 acyl group;p represents an integer of 0 to 7;R³ represents a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynylgroup, a (C3-6 cycloalkyl)-(CH₂)_(r)— group, or a (3- to 6-memberedsaturated heterocycle)-(CH₂)_(s)— group, said R³ may be substituted witha halogen;r represents an integer of 0 to 4;s represents an integer of 0 to 4;Ring 2 represents a 3- to 15-membered ring;R² represents a halogen, an oxo group, a hydroxyl group, a cyano group,C(O)R⁶, SO₂ R⁷, a C1-4 alkyl group, or a C1-4 alkoxy group,said C1-4 alkyl group or C1-4 alkoxy group may be substituted with asubstituent selected from the group consisting of a halogen, a hydroxylgroup, a cyano group, C(O)R⁸, NR⁹R¹ ⁰, and SO₂ R¹ ¹;R⁶ represents a hydroxyl group, a C1-4 alkyl group, a C1-4 alkoxy group,or NR¹ ²R¹ ³;R⁷ and R¹ ¹ each independently represent a hydroxyl group, a C1-4 alkylgroup, or a C3-6 cycloalkyl group, said C1-4 alkyl group may besubstituted with a halogen or CO₂R¹ ⁴;R⁸ represents a hydroxyl group, a C1-4 alkoxy group, or NR¹ ⁵ R¹ ⁶;R⁹, R¹ ⁰, R¹ ², and R¹ ³ each independently represent a hydrogen atom, aC1-4 acyl group, or a C1-4 alkyl group that may be substituted with NR¹⁵R¹ ⁶;R⁹ and R¹ ⁰, as well as R¹ ² and R¹ ³, taken together with the nitrogenatom to which they are attached, may form a 5- to 6-membered saturatedcyclic amine;R¹ ⁴ represents a hydrogen atom or a C1-4 alkyl group;R¹ ⁵ or R¹ ⁶ each independently represents a hydrogen atom, a C1-4alkyl, or a C1-4 acyl group;R¹ ⁵ and R¹ ⁶, taken together with the nitrogen atom to which they areattached, may form a 5- to 6-membered saturated cyclic amine;q represents an integer of 0 to 7;provided that when p and q each represent an integer of 2 or more, R¹and R² each independently may be the same or different);a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug ofany of these;

[2] The compound according to the above item [1], wherein q is 2 or 3;

[3] The compound according to the above item [1] or [2], wherein:

[4] The compound according to any one of the above items [1] to [3],which is represented by general formula (I-1):

(wherein:X represents CH or N;q-1 represents 2 or 3;all the other symbols represent the same meanings as symbols set forthin the above item [1]);

[5] The compound according to any one of the above items [1] to [4],wherein X is N;

[6] The compound according to any one of the above items [1] to [5],wherein Ring 1 is a 5- to 6-membered monocyclic aromatic ring or a 9- to10-membered bicyclic aromatic ring that may be partially saturated;

[7] The compound according to any one of the above items [1] to [6],wherein Ring 2 is a 5- to 6-membered monocyclic aromatic ring or a 9- to10-membered bicyclic aromatic ring that may be partially saturated;

[8] The compound according to the above item [1], wherein q is aninteger of 1 or more;

[9] The compound according to the above item [1] or [8], which isrepresented by general formula (I-a):

(wherein, all symbols represent the same meanings as symbols set forthin the above item [1]);

[10] The compound according to the above item [1] or [8], which isrepresented by general formula (I-b):

(wherein, all symbols represent the same meanings as symbols set forthin the above item [1]);

[11] The compound according to any one of the above items [1], [8], and[10], wherein R³ is a C3-4 branched alkyl group that may be substitutedwith a halogen;

[12] The compound according to any one of the above items [1], [8],[10], and [11], wherein Ring 2 is a benzene ring, and when q representsan integer of 1 or more, at least one R² is a halogen;

[13] The compound according to any one of the above items [1], [8],[10], and [11], wherein Ring 2 is a 5- to 6-membered monocyclic aromaticheterocycle;

[14] The compound according to the above item [1], which is representedby general formula (I-c):

(wherein, all symbols represent the same meanings as symbols set forthin the above item [1]);

[15]A compound, which is:

-   (1)    N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;-   (2)    N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(7-fluoro-1H-indazol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;-   (3)    3-(7-chloro-1H-indazol-4-yl)-N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;-   (4)    N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-3-(1H-indazol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;-   (5)    3-(7-fluoro-1H-indazol-4-yl)-N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;    or-   (6)    4-(4-amino-2-{[2-fluoro-4-(methylsulfonyl)phenyl]amino}-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indazole-7-carbonitrile;

[16] A compound, which is:

-   (1)    N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;-   (2)    N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(7-fluoro-1H-indazol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;-   (3)    3-(7-chloro-1H-indazol-4-yl)-N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;-   (4)    N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-3-(1H-indazol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;-   (5)    3-(7-fluoro-1H-indazol-4-yl)-N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;    or-   (6)    4-(4-amino-2-{[2-fluoro-4-(methylsulfonyl)phenyl]amino}-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indazole-7-carbonitrile;    a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug    of any of these;

[17] A pharmaceutical composition comprising the compound represented bygeneral formula (I) according to the above item [1], a salt thereof, asolvate thereof, an N-oxide thereof, or a prodrug of any of these as anactive ingredient;

[18] The composition according to the above item [17], which is a Brkinhibitor,

[19] The composition according to the above item [18], which is an agentfor preventing and/or treating cancer.

[20] The composition according to the above item [19], wherein thecancer is breast cancer, ovarian cancer, large bowel cancer, lungcancer, prostate cancer, head and neck cancer, melanoma, pancreaticcancer, bladder cancer, esophageal cancer, gastric cancer, or lymphoma;

[21] The composition according to the above item [19], wherein thecancer is breast cancer, ovarian cancer, large bowel cancer, lungcancer, prostate cancer, head and neck cancer, lymphoma, brain tumor,glioma, pituitary adenoma, uveal malignant melanoma, meningioma,thymoma, mesothelioma, esophageal cancer, gastric cancer, duodenalcancer, hepatocellular cancer, bile duct cancer, gallbladder cancer,pancreatic cancer, renal cell cancer, renal pelvis-ureteral cancer,bladder cancer, penile cancer, testicular cancer, uterine cancer,vaginal cancer, vulvar cancer, skin cancer, malignant bone tumor, softtissue sarcoma, chondrosarcoma, leukemia, myelodysplastic syndrome, andmultiple myeloma.

[22] A medicament comprising the compound represented by general formula(I) according to the above item [1], a salt thereof, a solvate thereof,an N-oxide thereof, or a prodrug of any of these in combination with atleast one kind selected from an alkylating agent, an antimetabolite, ananticancer antibiotic, a plant-derived preparation, a hormonepreparation, a platinum compound, a topoisomerase inhibitor, a kinaseinhibitor, an immune checkpoint inhibitor, an anti-CD20 antibody, ananti-HER2 antibody, an anti-EGFR antibody, and an anti-VEGF antibody;

[23] A method for preventing and/or treating cancer comprisingadministering an effective amount of the compound represented by generalformula (I) according to the above item [1], a salt thereof, a solvatethereof, an N-oxide thereof, or a prodrug of any of these to a patientin need of the prevention and/or treatment of cancer,

[24] A method for preventing and/or treating cancer comprisingadministering an effective amount of the compound represented by generalformula (I) according to the above item [1], a salt thereof, a solvatethereof, an N-oxide thereof, or a prodrug of any of these to a patientin need of the prevention and/or treatment of cancer, in combinationwith at least one kind selected from radiation therapy, chimeric antigenreceptor T cell therapy (CAR-T), thermotherapy, NK cell therapy, or NKTcell therapy;

[25] A method for inhibiting Brk comprising administering an effectiveamount of the compound represented by general formula (I) according tothe above item [1], a salt thereof, a solvate thereof, an N-oxidethereof, or a prodrug of any of these to a patient in need of theinhibition of Brk;

[26] The compound represented by general formula (I) according to theabove item [1], a salt thereof, a solvate thereof, an N-oxide thereof,or a prodrug of any of these for preventing and/or treating cancer; and

[27] Use of the compound represented by general formula (I) according tothe above item [1], a salt thereof, a solvate thereof, an N-oxidethereof, or a prodrug of any of these for the manufacture of an agentfor preventing and/or treating cancer.

Advantageous Effects of Invention

The compound of the present invention has a Brk inhibitory activity andhigh Brk selectivity as compared with other kinases, and therefore, is apreventive/therapeutic agent with excellent safety for diseases in whichBrk involves, for example, cancer.

DESCRIPTION OF EMBODIMENTS

The present invention is described in details hereinbelow.

In the description in translation of the present specification andclaims into a language such as English, unless otherwise defined, a termin a singular form encompasses that in a plural form, and a term in aplural form encompasses that in a singular form.

In the present specification, a “3- to 15-membered ring” refers to a “3-to 15-membered carbocycle” and a “3- to 15-membered heterocycle”.

In the present specification, a “3- to 15-membered carbocycle” refersto, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane,cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane,cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene,cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene,perhydropentalene, azulene, perhydroazulene, indene, perhydroindene,indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene,perhydronaphthalene, heptalene, perhydroheptalene, biphenylene,as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene,phenalene, phenanthrene, anthracene, spiro[4.4]nonane, spiro[4.5]decane,spiro[5.5]undecane, bicyclo[2.2.1]heptane, bicyclo[22.1]hept-2-ene,bicyclo[3.1.1]heptane, bicyclo[3.1.1]hept-2-ene, bicyclo[2.2.2]octane,bicyclo[2.2.2]oct-2-ene, bicyclo[4.2.0]octa-1,3,5-triene,2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthalene,6,7,8,9-tetrahydro-5H-benzo[7]annulene,5,6,7,8,9,10-hexahydrobenzo[8]annulene,2′,3′-dihydrospirocyclopropane-1,1′-indene,3′,4′-dihydro-2′H-spirocyclopropane-1,1′-naphthalene, adamantane,noradamantane, cubane rings and the like.

In the present specification, a “3- to 15-membered heterocycle” refersto, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan,pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzoxepin, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzazepine, benzodiazepine, benzofurazan, benzothiadiazole,benzotriazole, carbazole, β-carboline, acridine, phenazine,dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine,phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidine,aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin,tetrahydrooxepin, perhydrooxepin, thiirane, thietane, dihydrothiophene,tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran,dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline,isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroiobcnzothiophcne,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroqunoline, perhydroqunoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoine,dihydrocinoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine,tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine,tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole,perhydrocarbazole, dihydroacridine, tetrahydroacridine,perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene,tetrahydrodibenzofuran, tetrahydrodibenzothiophene,perhydrodibenzofiuran, perhydrodibenzothiophene, dioxolane, dioxane,dithiolane, dithiane, dioxaindane, benzodioxane, chromane,benzodithiolane, benzodithiane, azaspiro[4.4]nonane,oxazaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane,thiaspiro[4.5]decane, dithiaspiro[4.5]decane, dioxaspiro[4.5]decane,oxazaspiro[4.5]decane, azaspiro[5.5]undecane, oxaspiro[5.5]undecane,dioxaspiro[5.5]undecane, azabicyclo[2.2.1]heptane,oxabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane,azabicyclo[3.2.1]octane, oxabicyclo[3.2.1]octane,azabicyclo[2.2.2]octane, and diazabicyclo[2.2.2]octane rings and thelike.

In the present specification, a “halogen” refers to fluorine, chlorine,bromine, and iodine.

In the present specification, a “C1-4 alkyl group” refers to, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, and isobutyl groups.

In the present specification, a “C2-4 alkenyl group” refers to, forexample, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenylgroups and the like.

In the present specification, a “C2-4 alkynyl group” refers to, forexample, ethinyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl groups and the like.

In the present specification, a “C3-6 cycloalkyl group” refers tocyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

In the present specification, a “C1-4 alkoxy group” refers to methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, andisobutoxy groups.

In the present specification, a “C1-4 acyl group” refers to methanoyl,ethanoyl, propanoyl, butanoyl groups, and isomers thereof.

In the present specification, a “C3-4 branched alkyl group” refers toisopropyl, sec-butyl, tert-butyl, and isobutyl groups.

In the present specification, a “3- to 6-membered saturated heterocycle”refers to, for example, aziridine, azetidine, pyrrolidine, piperidine,oxirane, oxetane, oxolane (tetrahydrofuran), oxane (tetrahydropyran),thiirane, thietane, thiolane (tetrahydrothiophene), thiane(tetrahydrothiopyran), pyrazolidine, imidazolidine, dioxolane,dithiolane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,hexahydropyridazine, piperazine, dioxane, dithiane, morpholine,thiomorpholine rings and the like.

In the present specification, a “5- to 6-membered monocyclic aromaticring” refers to, for example, pyrrole, furan, thiophene, imidazole,pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole,oxadiazole, thiadiazole, furazan, tetrazole, benzene, pyridine,pyridazine, pyrimidine, pyrazine, triazine, tetrazine rings and thelike.

In the present specification, a “5- to 6-membered monocyclic aromaticheterocycle” refers to, for example, pyrrole, imidazole, triazole,tetrazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, thiadiazole, pyridine, pyrazine,pyrimidine, pyridazine rings and the like.

In the present specification, a “9- to 10-membered bicyclic aromaticring” refers to, for example, naphthalene, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indole, isoindole, indolizine,benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, indazole,benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, purine,quinoline, isoquinoline, phthalazine, pteridine, naphthyridine,quinoxaline, quinazoline, cinnoline, chromene, pyrrolopyridine,pyrazolopyridine, pyrrolopyrimidine, pyrazolopyrimidine,pyridopyrimidine, triazolopyridine, triazolopyrimidine, pyrazolotriazinerings and the like.

In the present specification, a “9- to 10-membered bicyclic aromaticring that may be partially saturated” refers to, for example,naphthalene, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, indole, isoindole, indolizine, benzoxazole,benzisoxazole, benzothiazole, benzisothiazole, indazole, benzimidazole,benzofurazan, benzothiadiazole, benzotriazole, purine, quinoline,isoquinoline, phthalazine, pteridine, naphthyridine, quinoxaline,quinazoline, cinnoline, chromene, pyrrolopyridine, pyrazolopyridine,pyrrolopyrimidine, pyrazolopyrimidine, pyridopyrimidine,triazolopyridine, triazolopyrimidine, pyrazolotriazine, indane,2,3-dihydrobenzofuran, 2,3-dihydrobenzothiophene, indoline,2,3-dihydro-1H-indazole rings and the like.

In the present specification, a “9- to 10-membered aromatic heterocycle”refers to, for example, indole, isoindole, indazole, purine,benzimidazole, benzotriazole, quinoline, isoquinoline, phthalazine,pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline rings andthe like.

In the present specification, a “5- to 6-membered saturated cyclicamine” refers to, for example, pyrrolidine, imidazolidine, triazolidine,tetrazolidine, piperidine, pyrazolidine, perhydropyrimidine, piperazine,perhydropyridazine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole(isoxazolidine), tetrahydrothiazole (thiazolidine),tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan,tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine,tetrahydrooxadiazine, tetrahydrothiadiazole (thiadiazolidine),tetrahydrothiazine, tetrahydrothiadiazine, morpholine, thiomorpholinerings and the like.

In the present specification,

is preferably,

and is more preferably,

In the present specification, Ring 1 is preferably a 5- to 6-memberedmonocyclic aromatic ring or a 9- to 10-membered bicyclic aromatic ringthat may be partially saturated, is more preferably an imidazole,pyrazole, oxazole, isoxazole, thiazole, isothiazole, benzene, pyridine,pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole,isoindole, benzoxazole, benzothiazole, indazole, benzimidazole,quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline,quinazoline, pyrrolopyridine, pyrazolopyridine, pyrrolopyrimidine,pyrazolopyrimidine, 2,3-dihydrobenzofuran, or pyridopyrimidine ring, isfurthermore preferably a benzene, pyridine, benzofuran, indole,indazole, benzothiazole, quinoline, isoquinoline, 2,3-dihydrobenzofuranor pyrrolopyridine ring, is especially preferably a 9- to 10-memberedaromatic heterocycle where heteroatoms contained therein are onlynitrogen, and is the most preferably an indole or indazole ring.

In the present specification, Ring 2 is preferably a 5- to 6-memberedmonocyclic aromatic ring or a 9- to 10-membered bicyclic aromatic ringthat may be partially saturated, is more preferably an imidazole,pyrazole, oxazole, isoxazole, thiazole, isothiazole, benzene, pyridine,pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole,indolizine, benzoxazole, benzothiazole, indazole, benzimidazole,benzofurazan, quinoline, isoquinoline, phthalazine, naphthyridine,quinoxaline, indane, indoline or quinazoline ring, is furthermorepreferably a pyrazole, thiazole, benzene, pyridine, indane, indoline orpyrimidine ring, is especially preferably a benzene or a 5- to6-membered monocyclic aromatic heterocycle, and is the most preferably abenzene or pyrazole ring.

In the present specification, a benzene ring of Ring 2 is preferably abenzene ring where in the case where q is an integer of 1 or more, atleast one R² is a halogen, and is more preferably a benzene ring wherein the case where q is an integer of 2 or more, R² is at least onehalogen and SO₂ R⁷.

In the present specification, R¹ is preferably a halogen, oxo, hydroxy,cyano, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl,methoxy, ethoxy, isopropoxy, difluoromethoxy, or trifluoromethoxy group,is more preferably a halogen, oxo, hydroxy, cyano, amino, methyl,trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy group,and is the most preferably a halogen or cyano group.

In the present specification, p is preferably an integer of 0 to 4, andis more preferably 0 or 1.

In the present specification, R³ is preferably a methyl, ethyl,isopropyl, tert-butyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl,cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl,cyclohexylmethyl, oxetanyl, oxetanylmethyl, oxolanyl, or oxolanylmethylgroup, is more preferably a difluoromethyl, isopropyl, tert-butyl,2,2,2-trifluoroethyl, cyclobutyl, cyclopentyl, or oxetanyl group, isfurthermore preferably a C3-4 branched alkyl group that may besubstituted with a halogen, and is especially preferably an isopropylgroup.

In the present specification, a C3-6 cycloalkyl in R³ group ispreferably a cyclobutyl or cyclopentyl group.

In the present specification, a 3- to 6-membered saturated heterocyclein R³ group is preferably an aziridine, azetidine, pyrrolidine,piperidine, oxirane, oxetane, oxolane (tetrahydrofuran), oxane(tetrahydropyran), thiirane, thietane, thiolane (tetrahydrothiophene),or thiane (tetrahydrothiopyran) ring, is more preferably an aziridine,azetidine, pyrrolidine, oxirane, oxetane, or oxolane (tetrahydrofuran)ring, and is especially preferably an oxetane ring.

In the present specification, r is preferably 0 or 1, and is morepreferably 0.

In the present specification, s is preferably 0 or 1, and is morepreferably 0.

In the present specification, R² is preferably a halogen, oxo, C(O)R⁶,SO₂ R⁷, a C1-4 alkyl or a C1-4 alkoxy group, the C1-4 alkyl or the C1-4alkoxy group may be substituted with a substituent selected from thegroup consisting of a halogen, a hydroxyl group, a cyano group, C(O)R⁸,NR⁹R¹ ⁰ and SO₂ R¹ ¹, is more preferably a halogen, oxo, acetyl,methylaminocarbonyl, dimethylaminocarbonyl, dimethylaminoethoxy,4-morpholinylmethyl, dimethylaminocarbonylmethyl,4-morpholinylcarbonylmethyl, piperidine-1-carbonyl,2-(dimethylamino)ethylcarbamoyl, carboxy, carboxymethyl,2-carboxypropan-2-yl, methyl, difluoromethyl, cyanomethyl,dimethylaminoethyl, morpholine-4-carbonyl, 2-hydroxy-2-methylpropyl,1,3-dihydroxy-2-methylpropan-2-yl, methoxy, 2-amino-2-oxoethyl,2-methoxy-2-oxoethyl, methylsulfonyl, methylsulfonylmethyl,cyclopropylsulfonyl, carboxymethylsulfonyl, or 3-(carboxymethyl)sulfonylgroup, and is especially preferably methyl, a halogen or amethylsulfonyl group.

In the present specification, R⁴ and R⁵ are preferably eachindependently a hydrogen atom.

In the present specification, R⁶ is preferably a hydroxyl group, a C1-4alkyl, or NR¹ ²R¹ ³, is more preferably methyl, a hydroxyl group, amine,methylamine, dimethylamine, piperidine, piperazine,dimethylaminoethylamine, or morpholine, and is especially preferablymethyl, a hydroxyl group, methylamine, dimethylamine, or piperazine.

In the present specification, R⁷ is preferably a C1-4 alkyl group or aC3-6 cycloalkyl group, is more preferably a methyl, ethyl, cyclopropyl,or cyclobutyl group, and is especially preferably a methyl orcyclopropyl group. Meanwhile, the above-described preferable R⁷, morepreferable R⁷, and especially preferable R⁷ may be each independentlysubstituted with CO₂R¹ ⁴.

In the present specification, R⁸ is preferably a hydroxyl group,methoxy, ethoxy, amine, methylamine, dimethylamine, piperidine,piperazine, or morpholine, and is more preferably a hydroxyl group,methoxy, amine, dimethylamine, or morpholine.

In the present specification, R⁹ and R¹ ⁰ are preferably eachindependently a hydrogen atom or methyl.

In the present specification, a 5- to 6-membered saturated cyclic aminethat is formed by R⁹ and R¹ ⁰, taken together with the nitrogen atom towhich they are attached, is preferably morpholine.

In the present specification, R¹ ¹ is preferably a methyl, ethyl, orcyclopropyl group, and is more preferably a methyl group.

In the present specification, R¹ ² and R¹ ³ are preferably eachindependently a hydrogen atom, methyl, or ethyl, and preferable R¹ ² andR¹ ³ may be each independently substituted with NR¹ ⁵ R¹ ⁶

In the present specification, a 5- to 6-membered saturated cyclic amineformed by R¹ ² and R¹ ³, taken together with the nitrogen atom to whichthey are attached, is preferably piperazine.

In the present specification, R¹ ⁵ and R¹ ⁶ are preferably eachindependently, a hydrogen atom, a methyl, or ethyl group.

In the present specification, a 5- to 6-membered saturated cyclic amineformed by R¹ ⁵ and R¹ ⁶, taken together with the nitrogen atom to whichthey are attached, is preferably morpholine.

In the present specification, q is preferably an integer of 1 or more,is more preferably an integer of 1 to 4, is furthermore preferably 2 or3, and is especially preferably 2.

In the present specification, X is preferably N.

In the present specification, general formula (I) is preferably acombination of the above-described preferable meaning of each of Ring 1,Ring 2, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹ ⁰, R¹ ¹, R¹ ², R¹ ³, R¹⁵, R¹ ⁶, p, q, r, s, and

In the present specification, general formula (I) is preferably acompound represented by general formula (I-a):

(wherein, all symbols represent the same meanings as symbols set forthin the above item [1]), a salt thereof, a solvate thereof, an N-oxidethereof, or a prodrug of any of these. Another preferable aspect is acompound represented by general formula (I-b):

(wherein, all symbols represent the same meanings as symbols set forthin the above item [1]), a salt thereof, a solvate thereof, an N-oxidethereof, or a prodrug of any of these. Another preferable aspect is acompound represented by general formula (I-c):

(wherein, all symbols represent the same meanings as symbols set forthin the above item [1]), a salt thereof, a solvate thereof, an N-oxidethereof, or a prodrug of any of these.

In the present specification, another preferable aspect of generalformula (I) is a compound represented by general formula (I-1):

(wherein, all symbols represent the same meanings as symbols set forthin the above item [1] or [4]), a salt thereof, a solvate thereof, anN-oxide thereof, or a prodrug of any of these, and a preferable aspectof general formula (I-1) is a compound represented by general formula(I-d):

(wherein, all symbols represent the same meanings as symbols set forthin the above item [1] or [4]), a salt thereof, a solvate thereof, anN-oxide thereof, or a prodrug of any of these. Another preferable aspectof general formula (I-1) is a compound represented by general formula(I-e):

(wherein, all symbols represent the same meanings as symbols set forthin the above item [1] or [4]), a salt thereof, a solvate thereof, anN-oxide thereof, or a prodrug of any of these, and a more preferableaspect is a compound represented by general formula (I-f):

(wherein, Ring 1-1 represents a 5- to 6-membered monocyclic aromaticring or a 9- to 10-membered bicyclic aromatic ring that may be partiallysaturated, and all the other symbols represent the same meanings assymbols set forth in the above item [1] or [4]) a salt thereof, asolvate thereof, an N-oxide thereof, or a prodrug of any of these.

Another more preferable aspect is a compound represented by generalformula (I-g):

(wherein, Ring 2-1 represents a 5- to 6-membered monocyclic aromaticring or a 9- to 10-membered bicyclic aromatic ring that may be partiallysaturated, and all the other symbols represent the same meanings assymbols set forth in the above item [1] or [4]), a salt thereof, asolvate thereof, an N-oxide thereof, or a prodrug of any of these, andis furthermore preferably a compound represented by general formula(I-h):

(wherein, Ring 1-1 represents a 5- to 6-membered monocyclic aromaticring or a 9- to 10-membered bicyclic aromatic ring that may be partiallysaturated, Ring 2-1 represents a 5- to 6-membered monocyclic aromaticring or a 9- to 10-membered bicyclic aromatic ring that may be partiallysaturated, and all the other symbols represent the same meanings assymbols set forth in the above item [1] or [4]), a salt thereof, asolvate thereof, an N-oxide thereof, or a prodrug of any of these.

In the present specification, in general formula selected from the groupof the above-described general formula (I-a), general formula (I-b),general formula (I-c), general formula (I-1), general formula (I-d),general formula (I-e), general formula (I-f), general formula (I-g), andgeneral formula (I-h), R³ is preferably each independently C1-4 alkyl,C3-6 cycloalkyl, and a 3- to 6-membered saturated heterocycle, is morepreferably methyl, ethyl, isopropyl, tert-butyl, cyclobutanyl, andcyclooxetanyl, is furthermore preferably a C3-4 branched alkyl groupthat may be substituted with a halogen, and is especially preferably anisopropyl group. The above-described preferable R³ and more preferableR³ may be substituted with a halogen.

In the present specification, another aspect of general formula (I) isthe most preferably all the compounds of the present invention describedin the following Examples, a salt thereof, a solvate thereof, an N-oxidethereof, or a prodrug of any of these.

In the present specification, unless otherwise specifically indicated,all isomers are included in the present invention. For example, an alkylgroup, an alkenyl group, an alkynyl group, an alkoxy group and the likeinclude linear and branched ones. In addition, all of isomers due toring(s) and fused ring(s) ((E)-, (Z)-, cis- and trans-forms), isomersdue to the presence of asymmetric carbon(s) and the like (R-, S-, α-and, β-forms, enantiomer(s) and diastereomer(s)), optically activesubstances having optical rotation (D-, L-, d- and l-forms), polarsubstances by chromatographic separation (more polar and less polarsubstances), compounds in equilibrium, rotational isomers, a mixturethereof in any proportion and a racemic mixture are included in thepresent invention. In addition, isomers due to tautomerism are allincluded in the present invention.

In the present specification, unless otherwise specified, the symbol:

represents that a substituent binds to the back side on the papersurface (in other words, α-configuration), the symbol:

represents that a substituent binds to the front side on the papersurface (in other words, β-configuration), and the symbol:

represents an arbitrary mixture of α-configuration and β-configuration,as would be apparent to those skilled in the art.

[Salts]

The compound represented by general formula (I) can be converted into asalt by a known method.

The salt is preferably a pharmaceutically acceptable salt.

The salt is preferably a water-soluble salt.

Examples of the salt include an acid addition salt, an alkali metalsalt, an alkaline earth metal salt, an ammonium salt, an amine salt andthe like.

Examples of the acid addition salt include an inorganic acid salt suchas a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, aphosphate and a nitrate as well as an organic acid salt such as anacetate, a lactate, a tartrate, a benzoate, a citrate, amethanesulfonate, an ethanesulfonate, a trifluoroacetate, abenzenesulfonate, a toluenesulfonate, an isethionate, a glucuronate anda gluconate.

Examples of the alkali metal salt include a potassium salt, a sodiumsalt and the like.

Examples of the alkaline earth metal salt include a calcium salt, amagnesium salt and the like.

Examples of the ammonium salt include a tetramethyl ammonium salt andthe like.

Examples of the amine salt include a triethylamine salt, a methylaminesalt, a dimethylamine salt, a cyclopentylamine salt, a benzylamine salt,phenethylamine salt, a piperidine salt, a monoethanolamine salt, adiethanolamine salt, a tris(hydroxymethyl)aminomethane salt, a lysinesalt, an arginine salt, an N-methyl-D-glucamine salt and the like.

In addition, the compound of the present invention can be converted intoan N-oxide by an arbitrary method. An N-oxide represents a compoundobtained by oxidating a nitrogen atom in the compound represented bygeneral formula (I). Specifically, an N-oxide refers to, when X, Y, andZ shown in general formula (I) each independently represent a nitrogenatom, a compound in which at least one of the nitrogen atom and nitrogenatoms in the pyrimidine is oxidated, when Ring 1, Ring 2, and asubstituent R³ are a nitrogen-containing heterocycle, a compound inwhich the nitrogen atom is oxidated, and when substituents R¹ and R²contain a nitrogen atom, a compound in which the nitrogen atom isoxidated.

The compound represented by general formula (I) and a salt thereof canbe also converted into a solvate.

The solvate is preferably a nontoxic and water-soluble solvate. Examplesof the appropriate solvate include a solvate of water and a solvate ofan alcohol based solvent (such as a solvate of ethanol). When a solvateis formed, the compound may be coordinated with an arbitrary number ofsolvent molecules.

[Prodrugs]

A prodrug of the compound represented by general formula (I) refers to acompound which is converted to the compound represented by generalformula (I) by a reaction caused by an enzyme, gastric acid and the likein vivo. Examples of the prodrug of the compound represented by generalformula (I) include the followings: when the compound represented bygeneral formula (I) has an amino group, a compound obtained by makingthe amino group in the compound represented by general formula (I) beacylated, alkylated, or phosphorylated (for example, a compound obtainedby making an amino group of the compound represented by general formula(I) be eicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated, tert-butylated and the like); when the compoundrepresented by general formula (I) has a hydroxyl group, a compoundobtained by making the hydroxy group in the compound represented bygeneral formula (I) be acylated, alkylated, phosphorylated or borated(for example, a compound obtained by making the hydroxy group in thecompound represented by general formula (I) be acetylated,palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated,alanylated, dimethylaminomethylcarbonylated and the like); and when thecompound represented by general formula (I) has a carboxy group, acompound obtained by making the carboxy group in the compoundrepresented by general formula (I) be esterified or amidated (forexample, a compound obtained by making the carboxy group in the compoundrepresented by general formula (I) be an ethyl ester, a phenyl ester, acarboxymethyl ester, a dimethylaminomethyl ester, a pivaloyloxymethylester, a 1-{(ethoxycarbonyl)oxy}ethyl ester, a phthalidyl ester, a(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester, a1-{[(cyclohexyloxy)carbonyl]oxy}ethyl ester, a methylamide or the like);and the like. These compounds can be prepared by a known method per se.In addition, the prodrug of the compound represented by general formula(I) may be either a solvate or a non-solvate. Further, the prodrug ofthe compound represented by general formula (I) may be a compound whichis converted to the compound represented by general formula (I) under aphysiological condition as described in “Iyakuhin no kaihatsu(Development of Medicaments)”, Vol. 7, “Bunshi sekkei (MolecularDesign)”, pages 163-198, published by Hirokawa-Shoten Ltd. in 1990.

Furthermore, each atom constituting the compound represented by generalformula (I) may also be replaced by an isotope (such as ²H, ³H, ¹ ³C, ¹⁴C, ¹ ⁵N, ¹ ⁶N, ¹ ⁷O, ¹ ⁸O, ¹ ⁸F, ³ ⁵S, ³ ⁶Cl, ⁷ ⁷Br, and ¹ ² ⁵I) andthe like.

[Processes for the Preparation of the Compound of the Present Invention]

The compound of the present invention represented by general formula (I)can be prepared by a known method. For example, the compound of thepresent invention can be prepared by appropriately improving methodsdescribed in Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd Edition (Richard C. Larock, JohnWiley & Sons Inc, 1999), methods equivalent thereto, or the methodsdescribed in Examples and the like or combining these methods.Meanwhile, in each of the following processes for the preparation, a rawmaterial compound may be used as a salt. Examples of the salt usedinclude those described as a pharmaceutically acceptable salt of thecompound represented by general formula (I).

Among the compounds of the present invention represented by generalformula (I), a compound in which:

can be prepared by a method shown by the following Reaction Scheme I.

(wherein, W represents a halogen, PG represents a protecting group of anamino group, BY₂ represents a boronic acid or a boronate ester, and theother symbols represent the same meanings as symbols set forth in theabove item [1] or [4]).

The compound of the present invention having an amino group, a carboxylgroup, or a hydroxyl group can be prepared as follows. The reactions toBuchwald-Hartwig reaction, or substitution reaction II shown in theabove-described Reaction Scheme I are conducted by using, as necessary,a compound protected by a protecting group which is generally used tothese groups, for example, a protecting group described in“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc,1999)”, and thereafter, a known deprotection reaction, or, for example,a deprotection reaction described in “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations 2nd Edition(Richard C. Larock, John Wiley & Sons Inc, 1999)” is conducted.

In the present specification, examples of the “protecting group of anamino group” when PG is a protecting group of an amino group include aprotecting group described in “Comprehensive Organic Transformations: AGuide to Functional Group Preparations 2nd Edition (Richard C. Larock,John Wiley & Sons Inc, 1999)”.

In Reaction Scheme I, a reaction step (halogenation) to prepare thecompound represented by general formula (III) from the compoundrepresented by general formula (II) can be performed by the methoddescribed in the present specification or a known method.

In Reaction Scheme I, a reaction step (amination) to prepare thecompound represented by general formula (IV) from the compoundrepresented by general formula (III) can be performed by the methoddescribed in the present specification or a known method.

In Reaction Scheme I, a reaction step (alkylation) to prepare thecompound represented by general formula (V) from the compoundrepresented by general formula (VI) can be performed by the methoddescribed in the present specification or a known method.

In Reaction Scheme I, a reaction step (deprotection) to prepare thecompound represented by general formula (VI) from the compoundrepresented by general formula (V) can be performed by the methoddescribed in the present specification or a known method.

In Reaction Scheme I, a reaction step (Suzuki-Miyaura coupling) toprepare the compound represented by general formula (VII) from thecompound represented by general formula (VI) can be performed by themethod described in the present specification or a known method.

In Reaction Scheme I, a reaction step (Buchwald-Hartwig reaction) toprepare the compound represented by general formula (I-2) from thecompound represented by general formula (VII) can be performed by themethod described in the present specification or a known method.

On the other hand, in Reaction Scheme I, the compound represented bygeneral formula (I-2) can be also prepared through a reaction step(substitution reaction I) to prepare the compound represented by generalformula (VIII) from the compound represented by general formula (VII), areaction step (oxidation reaction) to prepare the compound representedby general formula (IX) from the compound represented by general formula(VIII), substitution reaction II from the compound represented bygeneral formula (IX), and a deprotection reaction performed asnecessary. The above-described substitution reaction I, oxidationreaction, and substitution reaction II can be performed by the methoddescribed in the present specification or a known method.

Among the compounds of the present invention represented by generalformula (I), a compound in which:

can be prepared by a method shown by the following Reaction Scheme II.

(wherein, W represents a halogen, P represents a protecting group of anamino group, BY₂ represents each independently a boronic acid or aboronate ester, and the other symbols represent the same meanings assymbols set forth in the above item ([1]).

The compound of the present invention having an amino group, a carboxylgroup, or a hydroxyl group can be prepared as follows. Suzuki-Miyauracoupling reaction described in the above-described Reaction Scheme isconducted by using as necessary, a compound protected by a protectinggroup which is generally used to these groups, for example, a protectinggroup described in “Comprehensive Organic Transformations: A Guide toFunctional Group Preparations 2nd Edition (Richard C. Larock, John Wiley& Sons Inc, 1999)”, and thereafter, a known deprotection reaction, or,for example, a deprotection reaction described in “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations 2nd Edition(Richard C. Larock, John Wiley & Sons Inc, 1999)” is conducted.

In Reaction Scheme II, a reaction step (amination reaction) to preparethe compound represented by general formula (XI) from the compoundrepresented by general formula (X) can be performed by the methoddescribed in the present specification or a known method.

In Reaction Scheme II, a reaction step (Buchwald-Hartwig reaction) toprepare the compound represented by general formula (XII) from thecompound represented by general formula (XI) can be performed by themethod described in the present specification or a known method.

In Reaction Scheme II, a reaction step (halogenation reaction) toprepare the compound represented by general formula (XIII) from thecompound represented by general formula (XII) can be performed by themethod described in the present specification or a known method.

In Reaction Scheme II, a reaction step (Suzuki-Miyaura couplingreaction) to prepare the compound represented by general formula (XVI)from the compound represented by general formula (XIII) can be performedby the method described in the present specification or a known method.

In Reaction Scheme II, a reaction step (deprotection reaction) toprepare the compound represented by general formula (XV) from thecompound represented by general formula (XIV) can be performed by themethod described in the present specification or a known method.

In Reaction Scheme II, a reaction step (halogenation reaction) toprepare the compound represented by general formula (XVI) from thecompound represented by general formula (XV) can be performed by themethod described in the present specification or a known method.

In Reaction Scheme II, a reaction step (Suzuki-Miyaura couplingreaction) to prepare the compound represented by general formula (I-3)from the compound represented by general formula (XVI) can be performedby the method described in the present specification or a known method.

In Reaction Schemes I and II, an amination reaction is known, and forexample, is performed by using a corresponding amine compound, in anorganic solvent (such as methanol, ethanol, isopropanol,N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane,dichloromethane and chloroform) or in the absence of a solvent, in thepresence or absence of a base (such as triethylamine,diisopropylethylamine, cesium carbonate, potassium carbonate, and sodiumcarbonate), at 0° C. to under reflux.

In Reaction Schemes I and II, a halogenation reaction is known, and forexample, is performed by using a halogenating agent (such asN-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide,1,3-diiodo-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, and1,3-dichloro-5,5-dimethylhydantoin), in an organic solvent (such asdichloromethane, chloroform, methanol, tetrahydrofuran,N,N-dimethylformamide, acetonitrile, and ethyl acetate), in the presenceor absence of an acid (such as sulfuric acid, and acetic acid), at atemperature of −70° C. to 120° C.

In Reaction Schemes I and II, an alkylation reaction is known, and forexample, alkylation can be performed by subjecting the compound toMitsunobu reaction. Mitsunobu reaction is known, and for example, isperformed by using a corresponding alcohol compound, in an organicsolvent (such as dichloromethane, diethyl ether, tetrahydrofuran,acetonitrile, benzene, toluene, or a mixed solvent of 2 or more ofthem), in the presence of an azo compound (such as diethylazodicarboxylate (DEAD), diisopropyl azodicarboxylate,1,1′-(azodicarbonyl)dipiperidine, and1,1′-azobis(N,N-dimethylformamide)) and a phosphine compound (such astriphenylphosphine, tributylphosphine, trimethylphosphine, andpolymer-supported triphenylphosphine) at 0 to 60° C.

In addition, alkylation can be also performed by using an alkyl halide.Alkylation using an alkyl halide is known, and is performed by using acorresponding alkyl halide (such as an iodide, a bromide, and achloride), in an organic solvent (such as dichloromethane, chloroform,tetrahydrofuran, acetonitrile, and N,N-dimethylformamide), in thepresence of a base (such as triethylamine, diisopropylamine, potassiumcarbonate, and cesium carbonate), at 0° C. to under reflux.

In Reaction Schemes I and II, a deprotection reaction is known, and canbe performed as follows.

Examples of the protecting group of an amino group include abenzyloxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl(Alloc) group, a 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, atrifluoroacetyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl (Bn)group, a p-methoxybenzyl group, a benzyloxymethyl (BOM) group, a2-(trimethylsilyl)ethoxymethyl (SEM) group and the like.

The protecting group is not particularly limited to those describedabove as long as the protecting group can be eliminated easily andselectively. For example, protecting groups described in Green'sProtective Groups in Organic Synthesis, Fifth Edition (Peter G. M. Wuts,John Wiley & Sons Inc, 2014) are used.

A deprotection reaction of a protecting group is well known and examplesof the deprotection reaction include,

(1) alkaline hydrolysis;

(2) a deprotection reaction under an acidic condition;

(3) a deprotection reaction by hydrogenolysis;

(4) a deprotection reaction by using a fluoride ion;

(5) a deprotection reaction by using a metal;

(6) a deprotection reaction by using a metal complex; and the like.

These methods are described specifically as follows:

(1) A deprotection reaction by alkaline hydrolysis is performed, forexample, in an organic solvent (such as methanol, tetrahydrofuran anddioxane), by using a hydroxide of an alkali metal (such as sodiumhydroxide, potassium hydroxide, and lithium hydroxide), a hydroxide ofan alkaline earth metal (such as barium hydroxide and calciumhydroxide), a carbonate (such as sodium carbonate and potassiumcarbonate), an aqueous solution thereof or a mixture thereof at atemperature of 0 to 40° C.

(2) A deprotection reaction under an acidic condition is performed, forexample, in an organic solvent (such as dichloromethane, chloroform,dioxane, ethyl acetate, and anisole), in an organic acid (such as aceticacid, trifluoroacetic acid, methanesulfonic acid, and p-tosic acid), aninorganic acid (such as hydrochloric acid, and sulfuric acid) or amixture thereof (such as hydrobromic acid/acetic acid) at a temperatureof 0 to 100° C.

(3) A deprotection reaction by hydrogenolysis is performed, for example,in a solvent (such as an ethereal solvent (such as tetrahydrofuran,dioxane, dimethoxyethane and diethyl ether), an alcohol based solvent(such as methanol and ethanol), a benzene based solvent (such as benzeneand toluene), a ketone based solvent (such as acetone and methyl ethylketone), a nitrile based solvent (such as acetonitrile), an amide basedsolvent (such as dimethylformamide), water, ethyl acetate, acetic acidor a mixed solvent of two or more of them), in the presence of acatalyst (such as palladium on carbon, palladium black, palladiumhydroxide, platinum oxide and Raney nickel), under a hydrogen atmosphereat a normal pressure or under pressurization or in the presence ofammonium formate, at a temperature of 0 to 200° C.

(4) A deprotection reaction using a fluoride ion is performed, forexample, in a water-miscible organic solvent (such as tetrahydrofuran,and acetonitrile), by using tetrabutylammonium fluoride at a temperatureof 0 to 40° C.

(5) A deprotection reaction by using a metal is performed, for example,in an acidic solvent (such as acetic acid, a buffer solution of pH 4.2to 7.2 or a mixed solution of such a solution and an organic solventsuch as tetrahydrofuran), in the presence of powdery zinc at atemperature of 0 to 40° C., if necessary, while applying an ultrasonicwave.

(6) A deprotection reaction by using a metal complex is performed, forexample, in an organic solvent (such as dichloromethane,dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile,dioxane, and ethanol), water or a mixed solvent thereof, in the presenceof a trapping reagent (such as tributyltin hydride, triethylsilane,dimedone, morpholine, diethylamine and pyrrolidine), an organic acid(such as acetic acid, formic acid and 2-ethylhexanoic acid) and/or anorganic acid salt (such as sodium 2-ethylhexanoate and potassium2-ethylhexanoate), in the presence or absence of a phosphine-basedreagent (such as triphenylphosphine), by using a metal complex (such astetrakistriphenylphosphinepalladium(0),bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetateand chlorotris(triphenylphosphine)rhodium(I)), at a temperature of 0 to40° C.

In addition to the above-described methods, a deprotection reaction canbe performed, for example, by a method described in Green's ProtectiveGroups in Organic Synthesis, Fifth Edition (Peter G. M. Wuts, John Wiley& Sons Inc, 2014).

As those skilled in the art could easily understand, the compound of thepresent invention of interest can be easily prepared by using thesedeprotection reactions properly.

In Reaction Schemes I and II, Suzuki-Miyaura coupling reaction is known,and for example, is performed by conducting the reaction by using acorresponding boron compound, in an organic solvent (such as benzene,toluene, dimethylformamide, dioxane, tetrahydrofuran, methanol,acetonitrile, dimethoxyethane, and acetone), in the presence of a base(such as sodium ethylate, sodium hydroxide, potassium hydroxide,triethylamine, sodium carbonate, sodium bicarbonate, potassiumcarbonate, cesium carbonate, thallium carbonate, tripotassium phosphate,cesium fluoride, barium hydroxide, and tetrabutylammonium fluoride), anaqueous solution thereof, or a mixture thereof, in the presence of acatalyst (such as (tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄),bis(triphenylphosphine)palladium dichloride (PdCl₂ (PPh₃)₂), palladiumacetate (Pd(OAc)₂), palladium black,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl₂ (dppf)₂),diallylpalladium dichloride (PdCl₂ (allyl)₂), andphenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh₃)₂)) at roomtemperature to 120° C.

In Reaction Schemes I and II, Buchwald-Hartwig reaction is known, andfor example, is performed by conducting the reaction by using acorresponding amine compound, in an organic solvent (such as dioxane,toluene, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide,tert-butanol, or an appropriate mixed solvent of these organicsolvents), in the presence of a palladium catalyst (such as palladiumacetate, allylpalladium(II) chloride dimer (Pd₂ Cl₂ (allyl)₂), andtris(dibenzylideneacetone)dipalladium(0) (Pd₂ (dba)₃)), and a phosphorusligand (such as triphenylphosphine, tributylphosphine,tricyclohexylphosphine, Xantphos, and Xphos), in the presence of a base(such as potassium carbonate, cesium carbonate, sodium butoxide, andtripotassium phosphate), at a temperature of room temperature to about180° C.

In Reaction Scheme I, substitution reaction I is known, and isperformed, for example, by using a corresponding thiol or acorresponding metal thioalkoxide, in an organic solvent (such asdimethylsulfoxide, N,N-dimethylformamide, methanol, ethanol,isopropanol, and tetrahydrofuran), in water, or in a mixed solventthereof, in the presence or absence of a base (such as triethylamine,and diisopropylethylamine), at 0° C. to under reflux.

In Reaction Scheme I, an oxidation reaction of sulfur is known, and isperformed, for example, in an organic solvent (such as dichloromethane,chloroform, benzene, hexane, methanol, t-butyl alcohol, acetone,acetonitrile, tetrahydrofuran, acetic acid, and N,N-dimethylformamide),in water or in a mixed solvent thereof, in the presence of an excessoxidizing agent (such as hydrogen peroxide, sodium periodate, acylnitrite, sodium perborate, sodium hypochlorite, a peracid (such as3-chloroperbenzoic acid, and peracetic acid), oxone (trade name,hereinafter abbreviated as oxone; potassium peroxymonosulfate),potassium permanganate, chromic acid, and dimethyldioxolane), in thepresence or absence of an oxidation catalyst (such as hexaammoniumheptamolybdate tetrahydrate ((NH₄)₆ Mo₇ O₂₄.4H₂ O)) at a temperature of20 to 60° C.

In Reaction Scheme I, substitution reaction II is known, and isperformed, for example, by using a corresponding amine, in an organicsolvent (such as N,N-dimethylformamide, dimethylsulfoxide, ethanol,isopropanol, acetonitrile, and tetrahydrofuran), in the presence orabsence of a base (such as triethylamine, diisopropylamine, and sodiumtert-butoxide), at 0° C. to under reflux.

In Reaction Schemes, the compounds represented by general formula (II),general formula (X), general formula (R-1), general formula (R-2),general formula (R-2-2), and general formula (R-3) used as the startingmaterials are known or can be easily prepared by using a known method,for example, a method described in “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations 2nd Edition(Richard C. Larock, John Wiley & Sons Inc, 1999)”.

Among the compounds of the present invention represented by generalformula (I), compounds other than those described above can be preparedby combining the methods described in Examples in the presentspecification or a known method, for example, a method described in“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc,1999)”.

In the present specification, a reaction which involves heating in eachof the reactions can be performed by using a water bath, an oil bath, asand bath or a microwave as apparent to those skilled in the art.

In the present specification, a solid phase-supported reagent which issupported by a macromolecular polymer (such as polystyrene,polyacrylamide, polypropylene and polyethylene glycol) may be usedappropriately, in each of the reactions.

In the present specification, the reaction product in each of thereactions can be purified by a conventional purification means. Examplesof the purification means include distillation under a normal pressureor a reduced pressure, high performance liquid chromatography which usessilica gel or magnesium silicate, thin-layer chromatography, an ionexchange resin, a scavenger resin, column chromatography, or methodssuch as washing, recrystallization and the like. The purification may beperformed at each of reactions or may be performed after the completionof several reactions.

[Toxicity]

The toxicity of the compound of the present invention is low, andtherefore, the compound of the present invention can be used as amedicine safely.

[Application to Pharmaceuticals]

The compound of the present invention has a Brk inhibitory activity, andtherefore, the compound of the present invention is useful as an agentfor preventing and/or treating Brk-related diseases, for example, cancerand the like.

More specific examples of cancer include breast cancer, ovarian cancer,large bowel cancer (such as, colon cancer), lung cancer (such asnon-small-cell lung cancer), prostate cancer, head and neck cancer (suchas oral squamous cell cancer, head and neck squamous cell cancer,pharyngeal cancer, laryngeal cancer, tongue cancer, thyroid cancer, andacoustic schwannoma), lymphoma (such as B-cell lymphoma, and T-celllymphoma), brain tumor, glioma, pituitary adenoma, uveal malignantmelanoma, meningioma, thymoma, mesothelioma, esophageal cancer, gastriccancer, duodenal cancer, hepatocellular cancer, bile duct cancer,gallbladder cancer, pancreatic cancer, renal cell cancer, renalpelvis-ureteral cancer, bladder cancer, penile cancer, testicularcancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer (suchas malignant melanoma (melanoma)), malignant bone tumor, soft tissuesarcoma, chondrosarcoma, leukemia (such as acute myeloid leukemia, acutelymphocytic leukemia, chronic myeloid leukemia, and chronic lymphocyticleukemia), myelodysplastic syndrome, multiple myeloma and the like.

The compound of the present invention may be administered as a combinedagent by being combined with other drug(s) for the purpose of:

1) complementation and/or enhancement of the preventing and/or treatingeffect of the compound,

2) improvement in kinetics⋅absorption, and reduction of the dose of thecompound, and/or

3) reduction of the side effect of the compound.

The combined agent of the compound of the present invention with otherdrug(s) may be administered in the form of a compounding agent in whichboth ingredients are compounded in a preparation or may be administeredby means of separate preparations. The case of being administered bymeans of separate preparations includes concomitant administration andadministrations with a time difference. In addition, in the case of theadministrations with a time difference, the compound of the presentinvention may be firstly administered, followed by administration of theother drug(s). Alternatively, the other drug(s) may be firstlyadministered, followed by administration of the compound of the presentinvention. A method for administering the compound of the presentinvention and that for administering the other drug(s) may be the sameor different.

The disease against which the above-described combined agent exhibitsthe preventing and/or treating effect is not particularly limited aslong as the disease is that against which the preventing and/or treatingeffect of the compound of the present invention is complemented and/orenhanced.

Examples of the other drug(s) for complementation and/or enhancement ofthe preventing and/or treating effect of the compound of the presentinvention on cancer include an alkylating agent, an antimetabolite, ananticancer antibiotic, a plant-derived preparation, a hormonepreparation, a platinum compound, a topoisomerase inhibitor, a kinaseinhibitor, an immune checkpoint inhibitor, an anti-CD20 antibody, ananti-HER2 antibody, an anti-EGFR antibody, an anti-VEGF antibody, otheranticancer drugs and the like.

Examples of the alkylating agent include cyclophosphamide, ifosfamide,dacarbazine, nimustine hydrochloride, ranimustine, bendamustine,thiotepa, carboquone and the like.

Examples of the antimetabolite include methotrexate, pemetrexed,fluorouracil, tegafur, tegafur/uracil, tegafur/gimestat/potassiumotastat, doxifluridine, capecitabine, cytarabine, gemcitabinehydrochloride, fludarabine, nelarabine, carmofur, procarbazinehydrochloride and the like.

Examples of the anticancer antibiotic include mitomycin C, doxorubicinhydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride,epirubicin, chromomycin A3, bleomycin, peplomycin sulfate, therarubicinand the like.

Examples of the plant-derived preparation include irinotecanhydrochloride, etoposide, vincristine sulfate, vinblastine sulfate,vindesine sulfate, vinorelbine ditartrate, docetaxel hydrate, eribulinmesylate, paclitaxel and the like.

Examples of the hormone preparation include estramustine phosphatesodium, flutamide, bicalutamide, goserelin acetate, leuprorelin acetate,tamoxifen citrate, toremifene citrate, anastrozole, letrozole,exemestane, mepitiostane, medroxyprogesterone acetate, epitiostanol,fosfestrol, fadrozole hydrochloride hydrate, abiraterone, fulvestrant,aminoglutethimide and the like.

Examples of the platinum compound include carboplatin, cisplatin,nedaplatin, oxaliplatin and the like.

Examples of the topoisomerase inhibitor include topotecan, sobuzoxaneand the like.

Examples of the kinase inhibitor include an EGFR inhibitor includingerlotinib, gefitinib, and afatinib, an HER2 inhibitor includinglapatinib, a BCR-ABL inhibitor including imatinib, an ALK inhibitorincluding crizotinib, a multikinase inhibitor including regorafenib, anddasatinib and the like.

Examples of the immune checkpoint inhibitor include an anti-CTLA-4antibody including ipilimumab, an anti-PD-1 antibody includingnivolumab, and pembrolizumab, an anti-PD-L1 antibody includingRG7446/MPDL3280A, MSB0010718C, and MEDI4736 and the like.

Examples of the anti-CD20 antibody include rituximab, ibritumomab,ibritumomab tiuxetan, ocrelizumab and the like.

Examples of the anti-HER2 antibody include trastuzumab, trastuzumabemtansine, pertuzumab and the like.

Examples of the anti-EGFR antibody include cetuximab, panitumumab andthe like.

Examples of the anti-VEGF antibody include bevacizumab and the like.

A mass ratio of the compound of the present invention and other drug(s)is not particularly limited.

Arbitrary two or more kinds of other drugs may be administered incombination.

In addition, other drug(s) for complementation and/or enhancement of thepreventing and/or treating effect of the compound of the presentinvention includes not only that which has been found up to now but alsothat which will be found in future based on the above-describedmechanism.

Examples of other methods of treating to be combined with the compoundof the present invention for preventing and/or treating cancer includeradiation therapy (such as X-ray, γ-ray, electron beam, proton beam, andheavy ion), chimeric antigen receptor T cell therapy (CAR-T),thermotherapy, NK cell therapy, NKT cell therapy and the like.

In order to use the compound of the present invention as a single agentor as a combined agent which combines the compound of the presentinvention with other drug(s) for the purpose of the prevention and/ortreatment of the above-described disease, the substance which is anactive ingredient is normally formulated with various types ofpharmaceutically acceptable carriers such as additives and solvents andis administered systemically or locally in the form of an oralpreparation or a parenteral preparation. Here, a pharmaceuticallyacceptable carrier means a substance other than an active ingredientwhich is generally used for formulation of a medicine. It is preferablethat the pharmaceutically acceptable carrier does not exhibit apharmacological action in a dose of the formulation, is harmless, anddoes not interfere with a therapeutic effect of the active ingredient.In addition, the pharmaceutically acceptable carrier may also be usedfor the purpose of enhancing utility of the active ingredient and theformulation, making formulation easy, stabilizing quality, improvingusability or the like. Specifically, a substance described in “Iyakuhintenkabutsujiten (Japanese Pharmaceutical Excipients Directory)” (editedby Japan pharmaceutical Excipients Council), YAKUJI NIPPO LIMITEDpublished in 2000 or the like may be selected appropriately according toa purpose.

Dosage forms for administration includes, for example, oral preparation(e.g.: tablets, capsules, granules, powders, oral solutions, syrups,oral jelly agents, etc.), oro-mucosal preparation (e.g.: tablets fororo-mucosal application, sprays for oro-mucosal application, semi-solidpreparations for oro-mucosal application, gargles, etc.), preparationsfor injection (e.g.: injections, etc.), preparations for dialysis (e.g.:dialysis agents, etc.), preparation for inhalation (e.g.: inhalations,etc.), preparation for ophthalmic application (e.g.: ophthalmic liquidsand solutions, ophthalmic ointments, etc.), preparation for oticapplication (e.g.: ear preparation, etc.), preparations for nasalapplication (nasal preparations, etc.), preparation for recta (e.g.:suppositories, semi-solid preparations for rectal application, enemasfor rectal application, etc.), preparations for vaginal application(e.g.: tablets for vaginal use, suppositories for vaginal use, etc.) andpreparation for cutaneous application (e.g.: solid preparations forcutaneous application, liquids and solutions for cutaneous application,sprays, ointment, creams, gels, patches, etc.).

[Oral Preparation]

Oral preparation include, for example, tablets, capsules, granules,powders, liquids and solution for oral administration, syrups, Jelliesfor oral administration, etc. As oral preparation, there areImmediate-release dosage forms showing a release pattern of activesubstances that is not intentionally modified and modified-releasedosage forms are preparations showing modified pattern of activesubstances that is suitably modified for the desired purpose by means ofa specific formulation design and/or manufacturing methods.Modified-release dosage forms include enteric-coated andextended-release preparations. Enteric-coated (delayed-release)preparations release the bulk of the active substances not in stomachbut mainly in small intestine, in order to prevent degradation ordecomposition of the active substances in stomach or to decrease theirritation of the active substances on stomach. Enteric-coatedpreparations are generally coated with an acid-insoluble enteric film.Extended-release preparations are designed to control the release rateand release period of active substances and to restrict the release toappropriate sites in the gastrointestinal tracts in order to decreasethe dosing frequency and/or to reduce adverse or side effects.Extended-release preparations are generally prepared by using suitableagents that prolong the release of the active substances. Oral dosageforms such as capsules, granules and tablets can be coated withappropriate coating agents, such as sugars, sugar alcohols, or polymers,for the purpose of enabling the ingestion easy or of preventingdegradation of the active substances.

(1) Tablets

Tablets are solid preparation having a desired shape and size, intendedfor oral administration, and include orally disintegrating tablets,chewable tablets, effervescent tablets, dispersible tablets, solubletablets besides generally called tablets such as plain tablets,film-coated tablets, sugar-coated tablets, multi-layered tablets andpressure-coated tablets, etc. Plain tables are usually preparedaccording to the following methods (a), (b) and (c):

(a) Mix homogeneously active substances and excipients such as diluents,binders and disintegrators, granulate with water or a binder solution bysuitable methods, mix with a lubricant, and then compress into a desiredshape and size;

(b) Mix homogeneously active substances and excipients such as diluents,binders, and disintegrators, and then directly compress, or compressafter adding active substances and lubricant to granules previouslyprepared from excipients and then mixing homogeneously;(c) Mix homogeneously active substances and excipients such as diluentsand binders, moisten with a solvent, form into a certain shape and size,and then dry by suitable methods;Film-coated tablets can be prepared, usually, by coating plain tabletsusing suitable coating agents such as polymers. Sugar-coated tablets canbe prepared, usually, by coating plain tablets using suitable coatingagents including sugars and sugar alcohols. Multiple-layer tablets canbe prepared by compressing granules of different compositions to formlayered tablets by a suitable method. Pressure-coated tablets can beprepared by compressing granules to cover inner core tablets withdifferent compositions. In addition, tablets can be prepared as entericcoated tablets or timed-release tablet by suitable well-known methods.Orally disintegrating tablets, chewable tablets, effervescent tablets,dispersible tablets, soluble tablets are tablets which are addeddistinct role by selecting suitable excipients, and can be preparedaccording to said methods. Orally disintegrating tablets are tabletswhich are quickly dissolved or disintegrated in the oral cavity;Chewable tablets are tablets which are administered by chewing;Effervescent tablets are tablets which are quickly dissolved ordispersed with bubbles in water; Dispersible tablets are tablets whichare administered after having been dispersed in water; Soluble tabletsare tablets which are administered after having been dissolved in water.Effervescent tablets can be prepared using suitable acidic substancesand carbonates or hydrogen carbonates as excipients.

(2) Capsules

Capsules are preparations enclosed in capsules or wrapped with capsulebases, intended for oral administration. Capsules are classified intohard capsules and soft capsules. Hard capsules can be prepared by amethod where a homogeneous mixture of active substances with diluentsand other suitable excipients, or granules or formed masses prepared bya suitable methods, are filled into capsule shells as they are or afterslight compression. Soft capsules can be prepared by a method whereactive substances and suitable excipients are mixed, enclosed by asuitable capsule base such as gelatin plasticized by addition ofglycerin, D-sorbitol, etc. and molded in a suitable shape and size.Capsules can be prepared as enteric-coated or extended-release capsulesby a suitable well-known method. Coloring agents and preservatives, etc.may be added to the capsule bases.

(3) Granules

Granules are preparations prepared by granulation, and includeeffervescent granules besides generally called granules. Granules can beprepared by the following methods (a), (b), and (c);

(a) To powdery active substances add diluents, binders, disintegrators,or other suitable excipients, mix to homogenize, and granulate by asuitable method;

(b) To previously granulated active substances add excipients such asdiluents, and mix to homogenize;

(c) To previously granulated active substances add excipients such asdiluents, and granulate by a suitable method;

Granules can be coated if necessary, and can be prepared asenteric-coated or extended-release granules. Effervescent granules canbe prepared using suitable acidic substances and carbonates or hydrogencarbonates. Effervescent granules are granules which are quicklydissolved or dispersed with bubbles in water. Granules can be preparedas fine grain agents by adjusting particle size.

(4) Powders

Powders are preparations in powder form, and are usually prepared byhomogeneously mixing active substances with diluents or other suitableexcipients.

(5) Liquids and Solution for Oral Administration

Liquids and solution for oral administration are preparations in liquidform or flowable and viscous gelatinous state, and elixirs, suspensions,emulsions and lemonades are included in this category besides generallycalled Liquids and solution for oral administration. Liquids andsolution for oral administration are usually prepared by dissolving,emulsifying or suspending active substances in purified water togetherwith excipients, and by filtering if necessary. Elixirs are clear,sweetened and aromatic liquid preparations, containing ethanol, and areusually prepared by dissolving solid active substances or theirextractives in ethanol and purified water, adding aromatic agents andsucrose, other sugars or sweetening agents, and clarifying by filtrationor other procedure. Suspensions are liquid preparations of activesubstances suspended finely and homogeneously in a vehicle, and areusually prepared by adding suspending agent or other suitable excipientsand purified water or oil to solid active substances, and suspendinghomogeneously as the whole by a suitable method. Emulsions are liquidpreparations of active substances emulsified finely and homogeneously ina liquid vehicle, and are usually prepared by adding emulsifying agentsand purified water to liquid active substances, and emulsifying finelyand homogeneously by a suitable method. In addition, Lemonades are sweetand sour, clear liquid preparations, intended for oral administration.

(6) Syrups

Syrups are viscous liquid or solid preparations containing sugars orsweetening agents, and include preparation for syrups. Syrups areusually prepared by dissolving, mixing, suspending or emulsifying activesubstances in a solution of sucrose, other sugars or sweetening agents,or in simple syrup. Where necessary, the mixture is boiled, and filteredwhile hot. Preparations for syrups are preparations in form of granulesor powders, which becomes syrups by adding water. They may be termed“dry syrups”. Preparations for syrups are usually prepared with sugarsor sweetening agents according to said preparation method of granules orpowders.

(7) Jellies for Oral Administration

Jellies for oral administration are non-flowable gelatinous preparationshaving a certain shape and size, and usually prepared by mixing activesubstances with suitable excipients and polymer gel base, gelatinizingand forming into a certain shape and size by a suitable method.

[Preparation for Oro-Mucosal Application]

(1) Tablets for Oro-Mucosal Application

Tablets for oro-mucosal application are solid preparations having acertain form, and include troches/lozenges, sublingual tablets, buccaltablets, mucoadhesive tablets and medicated chewing gums. Preparationsfor oro-mucosal application are usually prepared according to saidmethod of tablets. Troches/lozenges are tablets for oro-mucosalapplication, which are gradually dissolved or disintegrated in themouth; Sublingual tablets are tablets for oro-mucosal application, fromwhich active substances are quickly dissolved sublingually and absorbedvia the oral mucosa; Buccal tablets are tablets for oro-mucosalapplications, from which the active substances are dissolved graduallybetween the cheek and teeth, and absorbed via the oral mucosa;Mucoadhesive tablets are tablets for oro-mucosal application that areapplied by adhesion to the oral mucosa; Medicated chewing gums aretablets for oro-mucosal application, releasing active substances bychewing.

(2) Spray for Oro-Mucosal Application

Spray for oro-mucosal application are preparation that are appliedactive substances by spraying into the oral cavity in mist, powder, foamor paste forms, and are usually prepared by dissolving or suspendingactive substances and suitable excipients in a solvent, filter, wherenecessary, and fill into a container together with liquefied orcompressed gas, or dissolving or suspending active substances andsuitable excipients in a solvent, and fill into a container, and fitwith a pump for spraying.

(3) Semi-Solid Preparations for Oro-Mucosal Application

Semi-solid preparations for oro-mucosal application are preparation incream, gel or ointment forms, intended for application to the oralmucosa. Semi-solid preparations for oro-mucosal application are usuallyprepared by emulsifying active substances together with excipients usingpurified water and oil component such as petrolatum, or by homogenizingactive substances together with suitable excipients using polymer gel oroil and fats as the base. Creams are semi-solid preparations, which arein the form of oil-in-water or water-in-oil emulsions. Hydrophobicpreparations in the form of water-in-oil emulsions may be termed “Oilycreams”. Creams are usually prepared by mixing homogeneously andemulsifying an oil-phase component and a water-phase component, bothwarmed, of which either one contains the active substances. Thesecomponents have the following constituents. Oil-phase component:Vaseline, fatty alcohols, etc., with or without emulsifying agents orother suitable excipients. Water-phase component: purified water with orwithout emulsifying agents or other suitable excipients. Gels aregelatinous preparations. There are aqueous gels and oily gels. Aqueousgels are usually prepared by adding polymers, other excipients andpurified water to active substances, dissolving or suspending, andgelatinizing by warming and cooling or by adding gelatinizing agents.Oily gels are usually prepared by adding liquid oily bases such asglycols, fatty alcohols and other excipients to active substances andmixing. Ointments are semi-solid preparations, which dissolve ordisperse active substances in a base. There are two types, hydrophobicointments and hydrophilic ointments. Hydrophobic ointments are usuallyprepared by warming to melt hydrophobic bases such as fatty oils, waxesor paraffin, adding and mixing active substances in the base to bedissolved or dispersed, and kneading the whole to make homogeneous.Hydrophilic ointments are usually prepared by warming to melthydrophilic bases such as macrogol, adding and mixing active substancesin the bases, and kneading the whole to make homogenous.

(4) Preparations for Gargle

Preparations for gargle are liquid preparations intended to applylocally to the oral and throat cavities. Solid type preparations to bedissolved in water before use are also included in this category.Preparations for gargle are usually prepared by dissolving activesubstances in a solvent together with suitable excipients, and filteringwhere necessary. Solid preparations are prepared according to saidmethod of tablets or granules.

[Preparation for Injection]

(1) Injections

Injections are sterile preparations to be administered directly into thebody through skin, muscle or blood vessel, usually in form of asolution, a suspension or an emulsion of active substances, or of asolid that contains active substances to be dissolved or suspendedbefore use, and include freeze-dried injections, powders, prefilledsyringes, cartridges, parenteral infusions, implants/pellets andprolonged-release injections besides generally called injections.Injections are prepared by the following method (a) and (b):

(a) Dissolve, suspend or emulsify active substances with or withoutexcipients in water for injection or an aqueous or non-aqueous vehiclehomogeneously, fill into containers for injection, seal, and sterilize.

(b) Dissolve, suspend or emulsify active substances with or withoutexcipients in water for injection or an aqueous or non-aqueous vehicle,and filtrate aseptically, or prepare aseptically a homogeneous liquid,fill into containers for injection, and seal; Freeze-dried injectionsare usually prepared by dissolving active substances with or withoutexcipients such as diluents in water for injection, sterilizing thesolution by aseptic filtration, filling the filtrate directly intoindividual containers for injection and being freeze-dried, or dividingthe filtrate in special containers, being freeze-dried and transferredinto individual containers for injection. Powder for injections areusually prepared by filtrating aseptically a solution of activesubstances, obtaining powders by crystallization from the solution ormixing additionally the powders with sterilized excipients, and fillingthe powders into individual containers for injections. Prefilledsyringes for injections are usually prepared by dissolving, suspendingor emulsifying active substances with or without excipients in avehicle, and filling into syringes. Cartridges are used by fixing in aninjection device for exclusive use. Cartridges for injection are usuallyprepared by dissolving, suspending or emulsifying active substances withor without excipients in a vehicle, and filling into cartridges.Parenteral infusions are usually injections of not less than 100 mL,intended for intravenous administration. Implants/Pellets are solid orgel-like form injections, intended for subcutaneous or intramuscularadministration by means of an implant device or operative treatment, forthe purpose of releasing active substances for a long period of time.Implants/Pellets are usually prepared in a form of pellet, microsphereor gel using biodegradable polymers. Prolonged release injections areinjections to be used for intramuscular administration, for the purposeof releasing active substances for a long period of time, and usuallyprepared by dissolving or suspending active substances in a non-aqueousvehicle such as vegetable oil, or by suspending microspheres preparedwith biodegradable polymers.

[Preparations for Dialysis]

(1) Dialysis Agents

Dialysis agents are preparations in liquid, or in solid which are to bedissolved before use, intended for peritoneal dialysis or hemodialysis,and include peritoneal dialysis agents and hemodialysis agents.Peritoneal dialysis agents are sterile dialysis agents, intended to beused for peritoneal dialysis, and are usually prepared by dissolvingactive substances with suitable excipients in a vehicle to make acertain volume, or by filling active substances combined with suitableexcipients in a container, and sealing it.

Sterilize if necessary. In the case of solid preparations to bedissolved before use, it can be prepared according to said preparationmethod of tablets or granules. Hemodialysis agents are dialysis agentsto be used for hemodialysis, and are usually prepared by dissolvingactive substances with excipients in a vehicle to make a certain volume,or by filling active substances with excipients in a container. In thecase of the solid preparations to be dissolved before use, it can beprepared according to said preparation method of tablets or granules.

[Preparation for Inhalation]

(1) Inhalations

Inhalations are preparations intended for administration as aerosols tothe bronchial tubes or lung. Inhalations are classified to dry powderinhalers, inhalation liquid preparations and metered-dose inhalers. Drypowder inhalers are preparations which deliver a constant respiratoryintake, intended for administration as solid particle aerosols, and areusually prepared by pulverizing active substances into fine particles.Where necessary, lactose or other suitable excipients are added to makehomogeneous mixture. Inhalation liquid preparations are liquidinhalations which are administered by an inhalation device such asoperating nebulizer. Inhalation liquid preparations are usually preparedby mixing active substances with a vehicle and suitable isotonic agentsand/or pH adjusting agents to make a solution or suspension, and byfiltering where necessary. Metered-dose inhalers are preparations whichdeliver a constant dose of active substances from the container togetherwith propellant filled in. Metered-dose inhalers are usually prepared bydissolving active substances with a suitable dispersing agents andstabilizers in a vehicle to make a solution or suspension, and byfilling in pressure-resistant containers together with liquidpropellant, and setting metering valves.

[Preparation for Ophthalmic Application]

(1) Ophthalmic Liquids and Solutions

Ophthalmic liquids and solutions are sterile preparations of liquid, orsolid to be dissolved or suspended before use, intended for applicationto the conjunctival sac or other ocular tissues. Ophthalmic liquids andsolutions are usually prepared by dissolving, suspending activesubstances in a vehicle after adding excipients to make a constantvolume, or mixing active substances and excipients, and filling intocontainers.

(2) Ophthalmic Ointments

Ophthalmic ointments are sterile preparations of semi-solid, intendedfor application to the conjunstival sac and other ocular tissues.Ophthalmic ointments are usually prepared by mixing homogeneouslysolution of or finely powdered active substances with petrolatum orother bases, and filling into containers.

[Preparation for Otic Application]

(1) Ear Preparation

Ear preparations are liquid, semi-solid, or solid preparations which areto be dissolved or suspended before use, intended for application to theexternal or internal ear. Ear preparations are usually prepared byfilling in containers with liquids in which active substances andexcipients are dissolved or suspended in a vehicle to make a constantvolume, or with powders in which active substances and excipients aremixed.

[Preparations for Nasal Application]

(1) Nasal Preparations

Nasal preparations are preparations intended for application to thenasal cavities or nasal mucous membrane. Nasal preparations areclassified into Nasal dry powder inhalers and Nasal liquid preparations.Nasal dry powder inhalers are fine powdered preparations, intended forapplication to the nasal cavities. Nasal dry powder inhalers are usuallyprepared by pulverizing active substances into moderately fineparticles, or by mixing homogeneously with excipients where necessary.Nasal liquids and solutions are liquid preparations, or solidpreparations to be dissolved or suspended before use, intended forapplication to the nasal cavities. Nasal liquids and solutions areusually prepared by dissolving or suspending active substances in avehicle together with excipients, and filtering where necessary.Isotonic agents and/or pH adjusting agents may be used.

[Preparations for Rectal Application]

(1) Suppositories for Rectal Application

Suppositories for rectal application are semi-solid preparations of adesired shape and size, intended for intrarectal application, whichrelease active substances by melting at body temperature or dissolvingor dispersing gradually in the secretions. Suppositories for rectalapplication are usually prepared by mixing homogeneously activesubstances and excipients such as dispersing agents and emulsifyingagents, dissolving or suspending uniformly in a base which is liquefiedby warming, filling a constant volume of the resultant material intocontainers, and molding it into a shape and size. Lipophilic bases orhydrophilic bases are usually used.

(2) Semi-Solid Preparations for Rectal Application

Semi-solid preparations for rectal application are preparations whichare in a form of cream, gel or ointment intended for application toaround or inside of the anus. Semi-solid preparations for rectalapplication are usually prepared by emulsifying active substances withexcipients in purified water and oil component such as Vaseline, or byhomogeneously mixing active substances and excipients in a base ofpolymer gel or grease. Creams for rectal application are usuallyprepared by mixing homogeneously and emulsifying an oil-phase component(such as vaseline, fatty alcohols, etc.) and a water phase component(such as purified water with or without emulsifying agents or othersuitable excipients), both warmed, of which either one contains theactive substances. Gels for rectal application are gelatinouspreparation. There are aqueous gels and oily gels. Aqueous gels areprepared adding polymers, other excipients and purified water to activesubstances, and dissolving or suspending, and gelatinizing by warmingand cooling or by adding gelatinizing agents. Oily gels are prepared byadding liquid oily bases such as glycols, fatty alcohols and otherexcipients to active substances and mixing. Ointments for rectalapplication are semi-solid preparations, which dissolve or disperseactive substances in a base. There are two types, hydrophobic ointmentand hydrophilic ointments. Hydrophobic ointments are usually prepared bywarming to melt hydrophobic bases such as fatty oils, waxes or paraffin,adding and mixing active substances in the bases to be dissolved ordispersed, and kneading the whole to make homogeneous. Hydrophilicointments are usually prepared by warming to melt hydrophilic bases suchas macrogol, adding and mixing active substances in the bases, andkneading the whole to make homogeneous.

(3) Enemas for Rectal Application

Enemas for rectal application are preparations in liquid form or viscousand gelatinous state, intended for applications via anus. Enemas forrectal application are preparations are usually prepared by dissolvingor suspending active substances in purified water or suitable aqueousvehicle to make a given volume, and filling in containers. Dispersingagents, stabilizers and/or pH adjusting agents may be used.

[Preparations for Vaginal Application]

(1) Tablets for Vaginal Use

Tablets for vaginal use are solid preparations of a desired shapes andsize, intended for application to the vagina, which release activesubstances by dissolving or dispersing gradually in the secretions.Tablets for vaginal use are usually prepared according to saidpreparation method of tablets.

(2) Suppositories for Vaginal Use

Suppositories for vaginal use are semi-solid preparations of a desiredshapes and size, intended for application to the vagina, which releaseactive substances by melting at body temperature or by dissolving ordispersing gradually in the secretions.

Suppositories for vaginal use are usually prepared according to saidpreparation method of suppositories for rectal applications.

[Preparation for Cutaneous Application]

(1) Solid Preparations for Cutaneous Application

Solid preparations for cutaneous application are solid preparationsintended for application to the skin (including scalp) or nails. Powdersfor cutaneous application are included in this category. Powders forcutaneous application are powdery solid preparations intended forexternal application. Powders for cutaneous application are usuallyprepared by mixing homogeneously active substances and excipients suchas diluents and pulverizing the mixture.

(2) Liquids and Solutions for Cutaneous Application

Liquids and solutions for cutaneous application are liquid preparationsintended for application to the skin (including scalp) or nails.Liniments and lotions are included in this category. Liquids andsolutions for cutaneous application are usually prepared by mixingactive substances and excipients in a vehicle, and filtering ifnecessary. Liniments are liquid or muddy preparations intended forexternal application to the skin by rubbing. Lotions are externalliquids in which active substances are dissolved, emulsified or finelydispersed in an aqueous vehicle. Lotions are usually prepared bydissolving, suspending or emulsifying active substances in purifiedwater with excipients and making homogeneous as a whole.

(3) Spray for Cutaneous Application

Spray for cutaneous application are preparations intended for sprayingactive substances onto the skin in mists, powders, forms or paste state.Spray for cutaneous application are classified into aerosols forcutaneous application and pump sprays for cutaneous application. Sprayfor cutaneous applications are usually prepared by dissolving orsuspending active substances in a vehicle, filtering where necessary,and filling in containers. Aerosols for cutaneous application are sprayswhich atomize active substances together with liquefied or compressedgas filled in containers. Aerosols for cutaneous application are usuallyprepared by dissolving or suspending active substances in a vehicle,filling with liquefied propellants in pressure-resistant containers, andsetting a continuous spray valve. If necessary, dispersing agents andstabilizer may be used. Pump sprays for cutaneous application are sprayswhich atomize active substances in containers by pumping. Pump spraysfor cutaneous application are usually prepared by dissolving orsuspending active substances with excipients in a vehicle, filling incontainers and setting pumps to the containers.

(4) Ointments

Ointments are semi-solid preparations to be applied to the skin, whichdissolve or disperse active substances in a base. There are two types,hydrophobic ointments and hydrophilic ointments. Hydrophobic ointmentsare usually prepared by warming to melt hydrophobic bases such as fattyoils, waxes or paraffin, adding and mixing active substances in the baseto be dissolved or dispersed, and Kneading the whole to makehomogeneous. Hydrophilic ointments are usually prepared by warming tomelt hydrophilic bases such as macrogol, adding and mixing activesubstances in the bases, and kneading the whole to make homogenous.

(5) Creams

Creams are semi-solid preparations to be applied to the skin, which arein the form of oil-in-water or water-in-oil emulsions. Hydrophobicpreparations in the form of water-in-oil emulsions may be termed “Oilycreams”. Creams are usually prepared by mixing homogeneously andemulsifying an oil-phase component and a water-phase component, bothwarmed, of which either one contains the active substances. Therecomponents have the following constituents. Oil-phase component:Vaseline, fatty alcohols, etc., with or without emulsifying agents orother suitable excipients. Water-phase component: purified water with orwithout emulsifying agents or other suitable excipients.

(6) Gels

Gels are gelatinous preparations intended for application to the skin.There are aqueous gels and oily gels. Aqueous gels are usually preparedby adding polymers, other excipients and purified water to activesubstances, dissolving or suspending, and gelatinizing by warming andcooling or by adding gelatinizing agents. Oily gels are usually preparedby adding liquid oily bases such as glycols, fatty alcohols and otherexcipients to active substances and mixing.

(7) Patches

Patches are preparations intended to be attached on the skin. Patchesare classified into Tapes/Plasters and Cataplasms/Gel patches. Patchesare usually prepared by mixing active substances homogeneously with abase such as a polymer or a mixture of polymers, spreading on a backinglayer or liner, and cutting into a given size. Percutaneous absorptiontype preparations may be prepared by using a release rate-controllingmembrane. Where necessary, adhesive agents or penetration enhancers maybe used. Tapes/Plasters are patches which are prepared with bases ofpractically no water contain. Tapes/Plasters are usually prepared bymixing homogeneously active substances with or without excipients and abase of non-water-soluble natural or synthetic polymers such as resins,plastics or rubber, and spreading on a cloth or spreading and sealing ona cloth or plastic film, cutting into a given size. The preparations maybe also prepared by filling a mixture of active substances and a basewith or without other excipients in releasers composed with arelease-controlling film, supporter and liner. Cataplasms/Gels arepatches using water containing bases. Cataplasms/Gels patches areusually prepared by mixing active substances, purified water, andglycerin or other liquid materials, or by mixing and kneading natural orsynthetic polymers, which are soluble in water or absorbent of water,with purified water, adding active substances, mixing the wholehomogeneously, spreading on a cloth or film, and cutting into a givensize.

EXAMPLES

The present invention is described in details by referring to Exampleshereinbelow, but the present invention is not limited to Examples.

Concerning chromatographic separation and TLC, a solvent in parenthesescorresponds to an eluting solvent or a developing solvent employed and aratio is expressed by volume ratio.

Concerning NMR, a solvent in parentheses corresponds to a solvent usedfor the measurement.

Silica gel column chromatography was performed by using YamazenAutomated Purification Equipment or Isco Combiflash Companion MPLCsystem.

HPLC preparative purification was performed under the followingcondition: [mobile phase (A): 0.1% trifluoroacetic acid aqueoussolution; mobile phase (B): 0.1% trifluoroacetic acid-acetonitrile].

LC-MS/ELSD was performed under the following condition:

[column: Waters ACQUITY C₁ ₈ (particle size: 1.7×10⁻⁶ m; column length:30×2.1 mm I.D.); flow rate: 1.0 mL/min; column temperature: 40° C.;mobile phase (A): 0.1% formic acid aqueous solution; mobile phase (B):0.1% formic acid-acetonitrile solution; gradient (the ratio of mobilephase (A):mobile phase (B) is described): [0 min] 95:5; [0.1 min] 95:5;[1.2 min] 5:95; [1.4 mini] 5:95; [1.41 min] 95:5; [1.5 min] 95:5;Detector: UV(PDA), ELSD, MS].

A compound name used in the present specification was given by using acomputer program ACD/Name (registered trademark) which generallydenominates a compound according to the IUPAC nomenclature, by usingChemdraw Ultra (Version 12.0, supplied by Cambridge Soft) or bydenominating according to the IUPAC nomenclature.

Reference Example 1: N-(1,3-dimethyl-1H-pyrazol-4-yl)formamide

To a solution of 1,3-dimethylpyrazol-4-amine hydrochloride (2 g) informic acid (10.2 mL), sodium formate (1.84 g) was added, and themixture was stirred at room temperature for 18 hours. To the reactionsolution, a saturated sodium bicarbonate aqueous solution was added, andthereafter, the solution was extracted with ethyl acetate. The obtainedorganic layer was washed with water and a saturated saline solution. Tothe aqueous layer, sodium chloride was added, and the mixture wasextracted with a mixed solution of dichloromethane and tetrahydrofuran.The organic layers were combined, and thereafter, were dried overanhydrous sodium sulfate, and were concentrated under a reducedpressure. The obtained residue was washed with methyl tert-butyl ether,and thereafter, was filtrated to give the title compound (1.41 g) havingthe following physical properties.

TLC: Rf 0.33 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ 2.20-2.24, 3.81-3.83, 6.60-6.94, 7.86, 8.30.

Reference Example 2: 4,6-Dichloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine

To a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (5.0 g) inacetonitrile (265 mL)/N,N-dimethylformamide (50 mL), N-iodosuccinimide(7.74 g) was added and the mixture was stirred at 80° C. for 16 hours.To the reaction solution, acetic acid (0.5 mL) was added, and thesolution was stirred for 9 hours. After acetonitrile was distilled offunder a reduced pressure, the residue was diluted with ethyl acetate. Tothe solution, a small amount of hexane, water, and a sodium sulfiteaqueous solution were added and the solution was stirred. To theobtained solution, water was added and the mixture was subjected to aliquid separation. The obtained organic layer was washed with water anda saline solution, and was dried over anhydrous sodium sulfate. To theobtained organic layer, a small amount of silica gel was added, and themixture was stirred and was filtrated. The filtrate was concentratedunder a reduced pressure to give the title compound (7.58 g) having thefollowing physical properties.

TLC: Rf 0.36 (hexane:ethyl acetate=4:1);

¹H-NMR (DMSO-d₆): δ11.13.

Reference Example 3:6-Chloro-3-iodo-N-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a suspended solution of the compound (6.5 g) prepared in ReferenceExample 2 in ethanol (50 mL), 4-methoxybenzylamine (2.97 mL) anddiisopropylethylamine (7.14 mL) were added at 0° C., and the mixture wasstirred at room temperature for 2 hours. The reaction solution wasconcentrated under a reduced pressure, and thereafter, ethyl acetate wasadded to the residue. The obtained solution was washed with water, asaturated sodium bicarbonate aqueous solution and a saturated salinesolution. The obtained organic layer was dried over anhydrous sodiumsulfate, and thereafter, was concentrated under a reduced pressure togive the title compound (6.5 g) having the following physicalproperties.

TLC: Rf 0.16 (hexane:ethyl acetate=4:1);

¹H-NMR (DMSO-d₆): δ3.76, 4.70-4.75, 6.92-6.98, 7.34-7.40, 7.51-7.59.

Reference Example 4:6-Chloro-3-iodo-N-(4-methoxybenzyl)-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of triphenylphosphine (3.91 g) in tetrahydrofuran (50 mL),diisopropyl azodicarboxylate (1.9 mol/L, 5.9 mL) was added at 0° C., andthe mixture was stirred for 10 minutes. To the reaction solution,isopropanol (0.86 mL) was added, and the solution was stirred at 0° C.for 10 minutes. To the reaction solution, the compound (3.1 g) preparedin Reference Example 3 was added, and the mixture was stirred at roomtemperature for 16 hours. The reaction solution was concentrated under areduced pressure, and thereafter, the obtained residue was purified bysilica gel column chromatography to give the title compound (3.0 g)having the following physical properties.

TLC: Rf 0.51 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ1.47-1.53, 3.82, 4.75-4.78, 4.97-5.09, 6.42-6.52,6.89-6.95, 7.30-7.36.

Reference Example 5:6-Chloro-3-iodo-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

The compound (3.0 g) prepared in Reference Example 4 was dissolved intrifluoroacetic acid (9.8 mL), and the solution was stirred at 60° C.for 16 hours. The reaction solution was concentrated under a reducedpressure, and thereafter, was azeotroped with toluene. The residue wasneutralized with 2 N sodium hydroxide aqueous solution, and the mixturewas extracted with ethyl acetate. The obtained organic layer was washedwith a saturated saline solution, and thereafter, was dried overanhydrous sodium sulfate. The organic layer was concentrated under areduced pressure, and thereafter, the residue was washed with methyltert-butyl ether. The obtained solid was taken by filtering to give thetitle compound (1.9 g) having the following physical properties.

TLC: Rf 0.26 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ1.48-1.56, 4.99-5.09, 5.75-6.10.

Reference Example 6:3-Iodo-6-(methylsulfanyl)-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of the compound (1.9 g) prepared in Reference Example 5 indimethylsulfoxide (50 mL), sodium thiomethoxide (473 mg) was added, andthe mixture was stirred at room temperature for 3 hours. To the reactionsolution, water was added, and the mixture was extracted with ethylacetate. The obtained organic layer was washed with water and asaturated saline solution, and was dried over anhydrous sodium sulfate.The solvent was distilled off under a reduced pressure to give the titlecompound (1.9 g) having the following physical properties.

TLC: Rf 0.29 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ1.48-1.55, 2.56, 4.97-5.09, 5.63-5.81.

Reference Example 7:3-Iodo-6-(methylsulfonyl)-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of the compound (1.97 g) prepared in Reference Example 6in acetonitrile (50 mL), ammonium molybdate tetrahydrate (348 mg) andhydrogen peroxide water (30^(%) aqueous solution, 3.16 mL) were added at0° C., and the mixture was stirred at room temperature for 18 hours. Thereaction solution was diluted with ethyl acetate, and thereafter, waswashed with water, and a saturated saline solution. The obtained organiclayer was dried over anhydrous sodium sulfate, and was concentratedunder a reduced pressure. The residue was washed with methyl tert-butylether, and thereafter, the solid was taken by filtering to give thetitle compound (1.62 g) having the following physical properties.

TLC: Rf 0.23 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ1.53-1.60, 3.33, 5.05-5.20, 6.10-6.45.

Reference Example 8:N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-iodo-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

To a solution of the compound (1.62 g) prepared in Reference Example 7in N,N-dimethylformamide (43 mL), the compound (1.18 g) prepared inReference Example 1 and sodium tert-butoxide (817 mg) were added at 0°C., and the mixture was stirred at 60° C. for 16 hours. To the reactionsolution, 2 N sodium hydroxide aqueous solution (21.2 mL) was added, andthe solution was stirred at room temperature for 1 hour. The reactionsolution was neutralized with 1 N hydrochloric acid, and thereafter, wasextracted with ethyl acetate. The obtained organic layer was washed witha saturated saline solution, and was dried over anhydrous sodiumsulfate. The solvent was distilled off under a reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (1.2 g) having the following physical properties.

TLC: Rf 0.43 (ethyl acetate);

¹H-NMR (CDCl₃): δ1.49-1.55, 2.24, 3.86, 4.82-4.95, 5.47-5.62, 6.33,7.81.

Reference Example 9:3-{1-[tert-Butyl(dimethyl)silyl]-1H-indol-5-yl}-N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

To a solution of the compound (250 mg) prepared in Reference Example 8in dimethylacetamide (5 mL), tripotassium phosphate (0.61 mL, 2 Maqueous solution) and 1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronicacid (CAS No. 913835-68-4) (200 mg) were added. The reaction solutionwas deaerated, and thereafter, to the solution,chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(a second generation XPhos precatalyst, CAS No. 1310584-14-5) (38 mg)was added under an argon atmosphere and the mixture was stirred at 80°C. for 2 hours. The reaction solution was diluted with ethyl acetate,and was washed with water, and a saturated saline solution. The obtainedorganic layer was dried over anhydrous sodium sulfate, and wasconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography to give the title compound (250 mg)having the following physical properties.

TLC: Rf 0.25 (ethyl acetate);

¹H-NMR (CDCl₃): δ0.09-0.12, 0.88-0.94, 1.55-1.63, 2.27, 3.87, 4.96-5.04,5.18-5.24, 6.32, 6.60-6.64, 7.26-7.30, 7.51-7.53, 7.90-7.96.

Example 1:N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

To a solution of the compound (250 mg) prepared in Reference Example 9in tetrahydrofuran (5 mL), tetra-n-butylammonium fluoride (0.97 mL, 1 Mtetrahydrofuran solution) was added, and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was diluted with ethylacetate, and was washed with a saturated ammonium chloride aqueoussolution and a saturated saline solution. The obtained organic layer wasdried over anhydrous sodium sulfate, and was concentrated under areduced pressure. The residue was purified by silica gel columnchromatography to give the compound of the present invention (115 mg)having the following physical properties.

TLC: Rf 0.41 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ1.58-1.64, 2.26, 3.87, 4.95-5.05, 5.18-5.26, 6.34,6.61-6.64, 7.25-7.30, 7.51, 7.90-7.95, 8.34.

Reference Example 10:4-Bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a solution of 4-bromo-7-fluoro-1H-indazole (918 mg) in methylenechloride (14 mL), 3,4-dihydro-2H-pyran (1.56 mL) and p-toluenesulfonicacid monohydrate (81 mg) were added, and the mixture was stirred at 40°C. for 1.5 hours. To the reaction solution, a saturated sodiumbicarbonate aqueous solution was added, and the solution was extractedwith ethyl acetate. The obtained organic layer was washed with asaturated saline solution, and thereafter, was dried over anhydroussodium sulfate, and was concentrated under a reduced pressure. Theresidue was purified by silica gel column chromatography to give thetitle compound (1.24 g) having the following physical properties.

TLC: Rf 0.61 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.48-1.82, 2.03-2.23, 2.51-2.68, 3.69-3.80, 4.00-4.08,5.83-5.90, 6.91-7.00, 7.17-7.23, 8.03-8.06.

Reference Example 11:[7-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]boronic acid

Under a nitrogen atmosphere, the compound (1.24 g) prepared in ReferenceExample 10 and triisopropylborate (3.8 mL) were dissolved intetrahydrofuran (16.6 mL), and the solution was cooled to −78° C. To thesolution, n-butyllithium (8.02 mL, 1.55 M/hexane) was added dropwise,and thereafter, the solution was stirred at −40° C. for 1 hour. To thereaction solution, water was added, and the organic layer wasback-extracted with 0.5 N sodium hydroxide aqueous solution. To theobtained aqueous layer, ammonium acetate (1.39 g) was added, and themixture was stirred at room temperature for 30 minutes. The reactionsolution was cooled to 0° C., and thereafter, to the solution, sodiumdihydrogenphosphate was added, and the pH was adjusted to 4 to 5. Theprecipitated solid was taken by filtering, and thereafter, was washedwith cold water. The obtained solid was dried to give the compound ofthe present invention (710 mg) having the following physical properties.

TLC: Rf 0.34 (hexane:ethyl acetate=2:1);

¹H-NMR (DMSO-d₆): δ 1.47-1.60, 1.63-1.82, 1.97-2.10, 2.35-2.54,3.58-3.69, 3.83-3.94, 5.79-5.85, 7.18-7.27, 7.58-7.64, 8.27, 8.34-8.37.

Reference Example 12:N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-[7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

A similar procedure to Reference Example 9 was carried out by using thecompound prepared in Reference Example 11 instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give the titlecompound having the following physical properties.

TLC: Rf 0.51 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ1.54-1.64, 1.72-1.83, 2.06-2.23, 2.26, 2.55-2.70,3.73-3.83, 3.88, 4.03-4.12, 4.98-5.16, 5.92-5.98, 6.34, 7.16-7.23,7.31-7.36, 7.88, 8.25-8.26.

Example 2:N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(7-fluoro-1H-indazol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

To a solution of the compound (61 mg) prepared in Reference Example 12in dichloromethane (1 mL), trifluoroacetic acid (0.9 mL) was added atroom temperature, and the mixture was stirred for 3 hours. To thereaction solution, a saturated sodium bicarbonate aqueous solution wasadded, and the solution was extracted with ethyl acetate. The obtainedorganic layer was washed with a saturated saline solution, andthereafter, was dried over anhydrous sodium sulfate, and wasconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography to give the compound of the presentinvention (34 mg) having the following physical properties.

TLC: Rf 0.27 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ1.60-1.66, 2.27, 3.88, 5.00-5.09, 5.12-5.22, 6.39,7.17-7.25, 7.34-7.40, 7.90, 8.33-8.36.

Example 3:3-(2,3-Dihydro-1-benzofuran-5-yl)-N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

A similar procedure to Reference Example 9 was carried out by using2,3-dihydrobenzofuran-5-boronic acid instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties.

¹H-NMR (DMSO-d₆): δ1.41-1.46, 2.12, 3.24-3.30, 3.73, 4.57-4.62,4.84-4.92, 6.10-6.40, 6.87-6.90, 7.32-7.36, 7.48, 7.93, 8.15.

Purity (LC-MS/ELSD): 99.3% (Retention time: 0.77 minutes);

MASS (ESI, Pos.): 405 (M+H)⁺.

Reference Example 13:N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-3-iodo-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

A similar procedure to Reference Example 1→Reference Example 8 wascarried out by using 2-fluoro-4-(methylsulfonyl)aniline instead of1,3-dimethylpyrazol-4-amine hydrochloride to give the title compoundhaving the following physical properties.

TLC: Rf 0.34 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ1.54-1.62, 3.05, 4.89-5.03, 5.58-5.82, 7.37-7.43,7.63-7.69, 7.75-7.79, 8.89-8.97.

Examples 4-1 to 4-4

A similar procedure to Reference Example 9→Example 2 was carried out byusing the compound prepared in Reference Example 13 instead of thecompound prepared in Reference Example 8, and using a correspondingboronic acid instead of 1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronicacid to give the compound of the present invention having the followingphysical properties.

Example 4-1:3-(7-Chloro-1H-indazol-4-yl)-N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

TLC: Rf 0.55 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ1.49-1.60, 3.23, 4.97-5.06, 6.38-7.15, 7.31-7.35,7.56-7.61, 7.68-7.79, 8.25, 8.66-8.73, 8.86, 13.74.

Example 4-2:N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-3-(1H-indazol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

TLC: Rf 0.43 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ1.65-1.71, 3.08, 5.08-5.20, 5.32-5.42, 7.42-7.47,7.51-7.62, 7.65-7.71, 7.77-7.82, 8.33, 9.01-9.08.

Example 4-3:3-(7-Fluoro-1H-indazol-4-yl)-N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

TLC: Rf 0.48 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ1.63-1.71, 3.08, 5.04-5.20, 5.27-5.40, 7.20-7.25,7.35-7.40, 7.41-7.43, 7.66-7.71, 7.79-7.85, 8.34-8.36, 9.00-9.07,10.35-10.50.

Example 4-4:4-(4-Amino-6-{[2-fluoro-4-(methylsulfonyl)phenyl]amino}-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indazole-7-carbonitrile

TLC: Rf 0.44 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-s): δ1.48-1.60, 3.22, 4.98-5.10, 7.44-7.48, 7.63-7.70,8.02-8.07, 8.35, 8.63-8.70, 8.90, 14.13.

Examples 5-1 to 5-5

A similar procedure to Reference Example 1→Reference Example 8→ReferenceExample 9→Example 2 was carried out by using a corresponding aminecompound instead of 1,3-dimethylpyrazol-4-amine hydrochloride and usinga corresponding boronic acid instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties. In Example 5-5, HPLC preparative purification was performedinstead of silica gel column chromatography in Example 2.

Example 5-1:3-(7-Fluoro-1H-indazol-4-yl)-1-isopropyl-N⁶-{3-methyl-1-[(methylsulfonyl)methyl]-1H-pyrazol-4-yl}-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

TLC: Rf 0.27 (ethyl acetate);

¹H-NMR (CDCl₃): δ1.60-1.66, 2.31, 2.90, 5.00-5.12, 5.24-5.36, 6.61,7.17-7.25, 7.34-7.40, 8.30-8.36.

Example 5-2:3-(7-Fluoro-1H-indazol-4-yl)-1-isopropyl-N⁶-[2-methoxy-4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

TLC: Rf 0.33 (hexane:ethyl acetate=1:2);

¹H-NMR (CD3 OD): δ1.60-1.65, 3.13, 4.06, 5.06-5.21, 7.24-7.31,7.35-7.38, 7.49, 7.58-7.63, 8.21-8.23, 8.98-9.01.

Example 5-3:N⁶-[4-(cyclopropylsulfonyl)-2-fluorophenyl]-3-(1H-indazol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

¹H-NMR (DMSO-d₆): δ1.04-1.06, 1.12-1.15, 1.53-1.55, 2.85-2.92,5.00-5.06, 7.34-7.36, 7.48-7.52, 7.62-7.75, 8.16, 8.70-8.75, 8.82,13.24.

Purity (LC-MS/ELSD): 100% (Retention time: 0.92 minutes);

MASS (ESI, Pos.): 507 (M+H)⁺.

Example 5-4:N⁶-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-(7-fluoro-1H-indazol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

TLC: Rf 0.42 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ1.62-1.68, 3.92, 5.00-5.15, 5.20-5.32, 6.64-6.71,7.18-7.25, 7.35-7.40, 8.09, 8.34-8.37.

Example 5-5:1-(4-{[4-Amino-3-(7-fluoro-1H-indazol-4-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino}-3-fluorophenyl)ethanonedi(trifluoroacetate)

¹H-NMR (CD3 OD): δ1.61-1.65, 2.59, 5.09-5.19, 7.26-7.31, 7.36-7.40,7.75-7.79, 7.88-7.91, 8.22-8.23, 8.86-8.92.

Purity (LC-MS/ELSD): 93.2% (Retention time: 0.95 minutes);

MASS (ESI, Pos.): 463 (M+H)⁺.

Examples 6-1 to 6-9

A similar procedure to Reference Example 1→Reference Example 8→ReferenceExample 9→Example 1 was carried out by using a corresponding aminecompound instead of 1,3-dimethylpyrazol-4-amine hydrochloride and usinga corresponding boronic acid instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties. In Examples 6-4 to 6-9, HPLC preparative purification wasperformed instead of silica gel column chromatography in Example 1.

Example 6-1:3-(1H-indol-5-yl)-1-isopropyl-N⁶-(3-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

TLC: Rf 0.35 (hexane:ethyl acetate=1:3);

¹H-NMR (CDCl₃): δ1.56-1.62, 2.31, 4.95-5.08, 5.23-5.37, 6.39, 6.61-6.64,7.27-7.31, 7.48-7.53, 7.94, 8.10, 8.28-8.35.

Example 6-2:N⁶-[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

TLC: Rf 0.26 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ1.60-1.65, 2.32, 4.95-5.05, 5.23-5.31, 6.42, 6.62-6.65,6.90-7.33, 7.50-7.54, 7.95, 8.28-8.34, 8.44.

Example 6-3:N⁶-(1,3-dimethyl-1H-pyrazol-5-yl)-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

TLC: Rf 0.40 (hexane:ethyl acetate=1:3);

¹H-NMR (CDCl₃): δ1.55-1.61, 2.28, 3.74, 4.92-5.04, 5.27-5.37, 6.15,6.55-6.66, 7.27-7.31, 7.47-7.54, 7.93, 8.26-8.34.

Example 6-4:3-(1H-indol-5-yl)-1-isopropyl-N⁶-(5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diaminetrifluoroacetate

Purity (LC-MS/ELSD): 85.0% (Retention time: 0.76 minutes);

MASS (ESI, Pos.): 386 (M+H)⁺.

Example 6-5:3-(1H-indol-5-yl)-1-isopropyl-N⁶-(6-methoxy-3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diaminetrifluoroacetate

Purity (LC-MS/ELSD): 96.4% (Retention time: 0.85 minutes);

MASS (ESI, Pos.): 415 (M+H)⁺.

Example 6-6:5-{[4-Amino-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino}-N,N-dimethyl-2-pyrimidinecarboxamidetrifluoroacetate

Purity (LC-MS/ELSD): 99.4% (Retention time: 0.76 minutes);

MASS (ESI, Pos.): 457 (M+H)⁺.

Example 6-7:N⁶-{4-[2-(dimethylamino)ethoxy]-2-fluorophenyl}-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diaminedi(trifluoroacetate)

Purity (LC-MS/ELSD): 99.9% (Retention time: 0.66 minutes);

MASS (ESI, Pos.): 489 (M+H)*.

Example 6-8:N⁶-[2-fluoro-(4-morpholinylmethyl)phenyl]-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diaminedi(trifluoroacetate)

Purity (LC-MS/ELSD): 99.5% (Retention time: 0.68 minutes);

MASS (ESI, Pos.): 501 (M+H)⁺.

Example 6-9:5-{[4-Amino-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino}-1-indanonetrifluoroacetate

Purity (LC-MS/ELSD): 100% (Retention time: 0.89 minutes);

MASS (ESI, Pos.): 438 (M+H)⁺.

Example 7:3-(6-Amino-5-methoxy-3-pyridinyl)-N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

A similar procedure to Reference Example 9 was carried out by using thecompound prepared in Reference Example 13 instead of the compoundprepared in Reference Example 8 and using6-amino-5-methoxypyridine-3-boronic acid pinacol ester instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties.

TLC: Rf 0.25 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ1.59-1.64, 3.06, 3.94, 4.86-4.94, 4.97-5.11, 5.36-5.42,7.23-7.26, 7.39-7.43, 7.62-7.69, 7.72-7.80, 7.95-7.97, 8.98-9.05.

Example 8:3-(1-Benzofuran-5-yl)-N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diaminedi(trifluoroacetate)

A similar procedure to Reference Example 4→Reference Example 5→ReferenceExample 6→Reference Example 7→Reference Example 8→Reference Example 9was carried out by using 2,2,2-trifluoroethanol instead of isopropanoland using benzofuran-5-boronic acid instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties. Meanwhile, HPLC preparative purification was performedinstead of silica gel column chromatography in Reference Example 9.

¹H-NMR (DMSO-d₆): δ2.13, 3.74, 5.02-5.13, 6.25-6.70, 7.07-7.08,7.57-7.59, 7.74-7.76, 7.92, 7.99, 8.08-8.09, 8.45.

Purity (LC-MS/ELSD): 99.7% (Retention time: 0.85 minutes);

MASS (ESI, Pos.): 443 (M+H)⁺.

Example 9:N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(7-fluoro-1H-indazol-4-yl)-1-(3-oxetanyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

A similar procedure to Reference Example 4→Reference Example 5→ReferenceExample 6→Reference Example 7→Reference Example 8→Reference Example9→Example 2 was carried out by using oxetan-3-ol instead of isopropanoland using the boronic acid prepared in Reference Example 11 instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties.

¹H-NMR (DMSO-d₆): δ2.13, 3.76, 4.98-5.02, 5.12-5.16, 5.89-5.96,6.30-6.80, 7.30-7.37, 8.03, 8.29-8.31, 8.45, 13.85.

Purity (LC-MS/ELSD): 99.0% (Retention time: 0.61 minutes);

MASS (ESI, Pos.): 435 (M+H)⁺.

Example 10:1-Cyclobutyl-N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(1H-indol-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diaminetrifluoroacetate

A similar procedure to Reference Example 4→Reference Example 5→ReferenceExample 6→Reference Example 7→Reference Example 8→Reference Example9→Example 1 was carried out by using cyclobutanol instead of isopropanoland using 1-(tert-butyldimethylsilyl)-1H-indol-6-ylboronic acid insteadof 1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties. Meanwhile, HPLC preparative purification was performedinstead of silica gel column chromatography in Example 1.

¹H-NMR (DMSO-d₆): δ1.83-1.90, 2.13, 2.36-2.41, 2.65-2.73, 3.76,5.14-5.22, 6.51-6.52, 7.29-7.31, 7.44-7.46, 7.67-7.70, 7.96, 8.25-8.50,11.27.

Purity (LC-MS/ELSD): 96.2% (Retention time: 0.81 minutes);

MASS (ESI, Pos.): 414 (M+H)⁺.

Reference Example 14:1-tert-Butyl-6-chloro-N-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (1.1 g) inethanol (25 mL), a suspension of t-butylhydrazine hydrochloride (620 mg)in ethanol (10 mL) and triethylamine (3.3 mL) were added slowly at −78°C., and the mixture was stirred at −78° C. for 2 hours. While stirringthe reaction solution, the temperature was raised over 2 hours to 0° C.,and the solution was stirred at 0° C. for 1 hour. To the reactionsolution, 4-methoxybenzylamine (656 mg) was added at 0*C, and thesolution was stirred at room temperature for 16 hours. To the reactionsolution, water, ethyl acetate, and hexane were added, the solution wasstirred, and the precipitate was taken by filtering. The filtrate wasextracted with ethyl acetate, and the organic layer was washed with asaturated saline solution. The obtained organic layer was dried overanhydrous sodium sulfate, and thereafter, was concentrated under areduced pressure. The residue was washed with ethyl acetate/hexane. Theresidue was combined with the precipitate taken by filtering previouslyto give the title compound (1.47 g) having the following physicalproperties.

TLC: Rf 0.35 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ1.76, 3.18, 4.70-4.76, 6.84-6.92, 7.21-7.34, 7.73.

Example 11:3-(7-Fluoro-1H-indazol-4-yl)-N⁶-[2-fluoro-4-(methylsulfonyl)phenyl]-1-(2-methyl-2-propanyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

A similar procedure to Reference Example 2→Reference Example 5→ReferenceExample 6→Reference Example 7→Reference Example 8→Reference Example9→Example 2 was carried out by using the compound prepared in ReferenceExample 14 instead of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine andusing the boronic acid prepared in Reference Example 11 instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties.

TLC: Rf 0.64 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ1.89, 3.08, 5.23-5.31, 7.17-7.25, 7.34-7.40, 7.41-7.45,7.65-7.71, 7.76, 7.82, 8.35-8.38, 8.97-9.03.

Example 12:4-{[4-Amino-1-cyclopentyl-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino}-3-fluoro-N,N-dimethylbenzamide

A similar procedure to Reference Example 1→Reference Example 4→ReferenceExample 5→Reference Example 6→Reference Example 7→Reference Example8→Reference Example 9 was carried out by using4-amino-3-fluoro-N,N-dimethylbenzamide instead of1,3-dimethylpyrazol-4-amine hydrochloride, using cyclopentanol insteadof isopropanol, and using 3-hydroxyphenylboronic acid instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties.

¹H-NMR (DMSO-d₆): δ1.65-1.68, 1.75-1.87, 2.02-2.12, 2.98, 5.00-5.11,6.84-6.87, 7.04-7.06, 7.24-7.26, 7.29-7.35, 8.20-8.27, 8.72, 9.60-9.75.

Purity (LC-MS/ELSD): 100% (Retention time: 0.89 minutes);

MASS (ESI, Pos.): 476 (M+H)⁺.

Examples 13-1 to 13-15

A similar procedure to Reference Example 1→Reference Example 2→ReferenceExample 3→Reference Example 4→Reference Example 5→Reference Example6→Reference Example 7→Reference Example 8→Reference Example 9→Example 2was carried out by using 1,3-dimethylpyrazol-4-amine hydrochloride or acorresponding amine compound instead of 1,3-dimethylpyrazol-4-aminehydrochloride, using 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine instead of4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine, and using a correspondingboronic acid instead of 1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronicacid to give the compound of the present invention having the followingphysical properties. Meanwhile, in Example 13-7, HPLC preparativepurification was performed instead of silica gel column chromatographyin Example 2.

Example 13-1:4-(4-Amino-2-{[2-fluoro-4-(methylsulfonyl)phenyl]amino}-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indazole-7-carbonitrile

TLC: Rf 0.18 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ1.59-1.64, 3.07, 4.94-5.08, 7.19, 7.27-7.31, 7.36-7.40,7.62-7.68, 7.75-7.80, 7.81-7.84, 8.27, 8.99-9.06.

Example 13-2:5-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-N,N-dimethyl-2-pyridinecarboxamide

TLC: Rf 0.32 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ1.54-1.61, 3.08-3.23, 4.90-5.12, 7.01, 7.07, 7.19-7.23,7.43-7.50, 7.68-7.72, 8.13, 8.23-8.27, 8.93-8.95, 10.21-10.36.

Example 13-3:1-(4-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methyl-1H-pyrazol-1-yl)-2-methyl-2-propanol

TLC: Rf 0.31 (ethyl acetate:methanol=9:1);

¹H-NMR (CD₃ OD): δ1.26, 1.57-1.62, 2.29, 4.09, 4.90-5.07, 7.20-7.23,7.42, 7.49-7.56, 7.59-7.63, 8.01, 8.08.

Example 13-4:2-(4-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methyl-1H-pyrazol-1-yl)-N,N-dimethylacetamide

TLC: Rf 0.40 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.52-1.58, 2.28, 3.00, 3.07, 4.85-5.03, 6.25, 6.99,7.19-7.23, 7.43-7.49, 8.08, 8.13.

Example 13-5:2-(4-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methyl-1H-pyrazol-1-yl)-1-(4-morpholinyl)ethanone

TLC: Rf 0.31 (ethyl acetate:methanol=9:1);

¹H-NMR (CD3 OD): δ1.54-1.61, 2.29, 3.60-3.64, 3.66-3.75, 4.95-5.04,5.08, 7.17, 7.19-7.22, 7.47-7.57, 8.06, 8.12.

Example 13-6:2-(4-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methyl-1H-pyrazol-1-yl)-2-methyl-1,3-propanediol

TLC: Rf 0.51 (ethyl acetate:methanol=10:1);

¹H-NMR (CD3 OD): δ1.57-1.62, 2.27, 3.83-3.88, 3.92-3.97, 4.95-5.02,7.16, 7.18-722, 7.46-7.56, 8.06, 8.16.

Example 13-7:6-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-1-methyl-1,3-dihydro-2H-indol-2-onetrifluoroacetate

TLC: Rf 0.35 (ethyl acetate, NH silica);

¹H-NMR (DMSO-d₆): δ1.56-1.62, 3.19, 3.56, 4.85-4.98, 7.13-7.00,7.02-7.27, 7.44-7.51, 7.54-7.60, 7.74, 8.14, 9.58-9.74, 13.10-13.36.

Example 13-8:[4-({4-Amino-7-isopropyl-5-[4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)-3-fluorophenyl](1-piperazinyl)methanone

TLC: Rf 0.28 (ethyl acetate:methanol=20:1, NH silica);

¹H-NMR (CDCl₃): δ1.53-1.58, 2.82-2.96, 3.55-3.75, 4.94-5.07, 6.93,7.16-7.27, 7.59-7.63, 7.68-7.73, 8.76-8.83.

Example 13-9:4-(4-Amino-2-{[2-fluoro-4-(1-piperazinylcarbonyl)phenyl]amino}-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile

TLC: Rf 0.24 (ethyl acetate:methanol=20:1, NH silica);

¹H-NMR (CDCl₃): δ1.44-1.60, 2.83-2.94, 3.57-3.72, 4.86-5.04, 6.96,7.15-7.27, 7.57-7.62, 7.69-7.76, 8.74-8.81.

Example 13-10:[4-({4-Amino-7-isopropyl-5-[4-(trifluoromethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)-3-fluorophenyl](1-piperazinyl)methanone

TLC: Rf 0.23 (ethyl acetate:methanol=20:1, NH silica);

¹H-NMR (CDCl₃): δ1.51-1.58, 2.92-3.01, 3.63-3.78, 4.96-5.08, 6.88,7.17-7.34, 7.48-7.56, 8.76-8.83.

Example 13-11:(4-{[4-Amino-7-isopropyl-5-(3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-fluorophenyl1-piperazinyl)methanone

TLC: Rf 0.20 (ethyl acetate:methanol=20:1, NH silica);

¹H-NMR (CDCl₃): δ1.52-1.57, 2.82-2.94, 3.50-3.70, 3.86, 4.92-5.10,6.85-6.91, 7.00-7.03, 7.04-7.12, 7.13-7.25, 7.34-7.40, 8.76-8.84.

Example 13-12:N²-(1,3-dimethyl-1H-pyrazol-4-yl)-5-(6-fluoro-1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.60 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ1.52-1.58, 2.72, 3.86, 4.80-5.04, 6.21, 6.98-7.04,7.05-7.12, 7.91, 8.10.

Example 13-13:N²-(1,3-dimethyl-1H-pyrazol-4-yl)-7-isopropyl-5-(6-methyl-1H-indazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.20 (ethyl acetate:methanol=20:1);

¹H-NMR (DMSO-d₆): δ1.40-1.48, 2.11, 2.45, 3.72, 4.80-4.93, 5.55-6.05,6.90, 7.20-7.30, 7.48-7.68, 7.85-7.98, 12.98.

Example 13-14:N²-(1,3-dimethyl-1H-pyrazol-4-yl)-7-isopropyl-5-(7-methyl-1H-indazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.51 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ1.52-1.58, 2.27, 2.60, 3.86, 4.82-5.04, 6.22, 6.95,7.12-7.18, 7.21-7.30, 7.92, 8.13.

Example 13-15:N²-(1,3-dimethyl-1H-pyrazol-4-yl)-7-isopropyl-5-(5-methyl-1H-indazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.27 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ1.48-1.60, 2.26, 2.37, 3.85, 4.48-4.62, 4.91-5.06,6.26, 6.80, 7.26, 7.32-7.43, 7.82, 7.92.

Examples 14-1 to 14-13

A similar procedure to Reference Example 1→Reference Example 2→ReferenceExample 3→Reference Example 4→Reference Example 5→Reference Example6→Reference Example 7→Reference Example 8→Reference Example 9 wascarried out by using 1,3-dimethylpyrazol-4-amine hydrochloride or acorresponding amine compound instead of 1,3-dimethylpyrazol-4-aminehydrochloride, using 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine instead of4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine and using a correspondingboronic acid instead of 1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronicacid to give the compound of the present invention having the followingphysical properties.

Example 14-1:5-(1-Benzofuran-3-yl)-N²-(1,3-dimethyl-1H-pyrazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.65 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ1.50-1.60, 2.26, 3.86, 4.82-5.02, 6.24, 6.90,7.22-7.44, 7.54-7.59, 7.61-7.65, 7.72, 7.91.

Example 14-2:5-(1,2-Benzothiazol-5-yl)-N²-(1,3-dimethyl-1H-pyrazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.54 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ1.48-1.58, 2.27, 3.87, 4.84-5.02, 6.18-6.23, 6.87,7.68-7.72, 7.91, 8.01-8.05, 8.16-8.17, 8.95.

Example 14-3:5-(2,1-Benzothiazol-5-yl)-N²-(1,3-dimethyl-1H-pyrazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.23 (ethyl acetate);

¹H-NMR (CDCl₃): δ1.51-1.57, 2.27, 3.86, 4.88-5.02, 6.20, 6.89,7.61-7.66, 7.84, 7.89-7.94, 9.18.

Example 14-4:N²-(1,3-dimethyl-1H-pyrazol-4-yl)-7-isopropyl-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.36 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ1.51-1.58, 2.27, 3.86, 4.79-4.83, 4.91-5.02, 6.17,6.83, 7.14-7.18, 7.37-7.40, 7.93, 7.98-8.01, 8.37-8.40, 8.79.

Example 14-5:5-(4-Amino-2-{[2-fluoro-4-(methylsulfonyl)phenyl]amino}-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1(2H)-isoquinolinone

TLC: Rf 0.27 (ethyl acetate);

¹H-NMR (CD3 OD): δ1.56-1.64, 3.13, 4.98-5.07, 6.43-6.67, 7.12,7.13-7.17, 7.58-7.79, 8.36-8.41, 9.08-9.16.

Example 14-6:N²-[2-fluoro-4-(methylsulfonyl)phenyl]-7-isopropyl-5-(5-quinolinyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.23 (ethyl acetate);

¹H-NMR (CDCl₃): δ1.52-1.68, 3.07, 4.52-4.62, 4.98-5.10, 6.98, 7.31-7.38,7.39-7.44, 7.60-7.67, 7.74-7.82, 8.15-8.19, 8.28-8.32, 8.95-8.99,9.01-9.09.

Example 14-7:Methyl(4-{[4-amino-5-(1-benzofuran-5-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methyl-1H-pyrazol-1-yl)acetate

TLC: Rf 0.50 (ethyl acetate);

¹H-NMR (CDCl₃): δ1.49-1.55, 2.29, 3.78, 4.86, 4.90-5.00, 6.26,6.78-6.81, 7.39-7.43, 7.54-7.59, 7.67-7.70, 8.05.

Example 14-8:5-(1-Benzofuran-5-yl)-N²-(1,5-dimethyl-1H-pyrazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.58 (ethyl acetate);

¹H-NMR (CDCl₃): δ1.44-1.51, 2.23, 3.80, 4.83-5.02, 6.01, 6.77,6.78-6.81, 7.39-7.44, 7.53-7.58, 7.66-7.70, 7.84.

Example 14-9:5-(1-Benzofuran-5-yl)-N²-[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.56 (hexane:ethyl acetate=2:3);

¹H-NMR (CDCl₃): δ1.53-1.60, 2.32, 4.89-5.03, 6.29, 6.79-6.84, 7.40-7.45,7.55-7.61, 7.65-7.72, 8.45.

Example 14-10:5-(1-Benzofuran-5-yl)-N²-(2,5-dimethyl-1,3-thiazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.25 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ1.52-1.59, 2.37, 2.63, 4.89-5.03, 6.59-6.66, 6.80-6.84,7.39-7.43, 7.56-7.60, 7.67-7.71.

Example 14-11:5-(1-Benzofuran-5-yl)-7-isopropyl-N²-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.48 (hexane:ethyl acetate=1:4);

¹H-NMR (CDCl₃): δ1.46-1.54, 3.77, 3.96, 4.80-5.01, 6.32, 6.70-6.81,7.40-7.44, 7.54-7.58, 7.66-7.70, 7.86.

Example 14-12:5-[4-(Difluoromethoxy)phenyl]-N²-[2-fluoro-4-(methylsulfonyl)phenyl]-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

TLC: Rf 0.33 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ1.53-1.58, 3.07, 4.92-5.03, 6.32-6.81, 6.89, 7.18-7.27,7.28-7.34, 7.47-7.51, 7.62-7.67, 7.73-7.77, 9.00-9.07.

Example 14-13:4-{[4-Amino-5-(4-chloro-3-methoxyphenyl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-fluoro-N-methylbenzamide

TLC: Rf 0.47 (hexane:ethyl acetate=1:4);

¹H-NMR (CDCl₃): δ1.50-1.60, 3.00-3.03, 3.96, 4.92-5.03, 6.00-6.08, 6.89,7.00-7.12, 7.18-7.21, 7.40-7.45, 7.52-7.59, 8.80-8.86.

Reference Example 15: Methyl4-{[4-amino-5-(1-benzofuran-5-yl)-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-fluorobenzoate

A similar procedure to Reference Example 1→Reference Example 2→ReferenceExample 3→Reference Example 4→Reference Example 5→Reference Example6→Reference Example 7→Reference Example 8→Reference Example 9 wascarried out by using methyl 4-amino-3-fluorobenzoate instead of1,3-dimethylpyrazol-4-amine hydrochloride, using2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine instead of4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine, and usingbenzofuran-5-boronic acid instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give the titlecompound having the following physical properties.

TLC: Rf 0.81 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ1.55-1.62, 3.90, 4.93-5.06, 6.81, 6.89, 7.22-7.28,7.40-7.44, 7.56-7.61, 7.64-7.77, 7.84-7.91, 8.84-8.92.

Example 15:4-{[4-Amino-5-(1-benzofuran-5-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-fluorobenzoicacid

To a solution of the compound (113 mg) prepared in Reference Example 15in ethanol (5 mL), 2 N sodium hydroxide aqueous solution (1 mL) wasadded, and the mixture was stirred at 40° C. for 3 hours. The reactionsolution was neutralized with 2 N hydrochloric acid, and thereafter, wasextracted with ethyl acetate. The obtained organic layer was dried overanhydrous sodium sulfate, and was concentrated under a reduced pressure.The residue was purified by silica gel column chromatography to give thecompound of the present invention (65 mg) having the following physicalproperties.

TLC: Rf 0.45 (hexane:ethyl acetate=2:3);

¹H-NMR (DMSO-d₆): δ1.43-1.49, 4.80-4.95, 6.00-6.30, 6.96-7.00, 7.26,7.36-7.42, 7.60-7.76, 8.00-8.03, 8.25-8.43, 8.60-8.71.

Example 16:[(4-{[4-Amino-5-(1-benzofuran-5-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-fluorophenyl)sulfonyl]aceticacid

A similar procedure to Reference Example 1→Reference Example 2→ReferenceExample 3→Reference Example 4→Reference Example 5→Reference Example6→Reference Example 7→Reference Example 8→Reference Example 9→Example 15was carried out by using ethyl[(4-amino-3-fluorophenyl)sulfonyl]acetateinstead of 1,3-dimethylpyrazol-4-amine hydrochloride, using2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine instead of4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine and using benzofuran-5-boronicacid instead of 1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid togive the compound of the present invention having the following physicalproperties.

TLC: Rf 0.40 (ethyl acetate:methanol=3:1);

¹H-NMR (DMSO-d₆): δ1.40-1.50, 4.44, 4.87-4.98, 5.95-6.18, 6.98-7.01,7.25, 7.37-7.42, 7.63-7.75, 8.00-8.02, 8.45-8.50, 8.81-8.90.

Example 17:N²-(1,3-dimethyl-1H-pyrazol-4-yl)-5-(1H-indol-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

A similar procedure to Reference Example 1→Reference Example 2→ReferenceExample 3→Reference Example 4→Reference Example 5→Reference Example6→Reference Example 7→Reference Example 8→Reference Example 9→Example 1was carried out by using 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidineinstead of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine, and using1-(toluene-4-sulfonyl)-1H-indole-3-boronic acidN-tert-butyldimethylsilyl protected product instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties.

TLC: Rf 0.40 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ1.50-1.57, 2.26, 3.86, 4.81-5.02, 6.22, 6.84,7.13-7.21, 7.25-7.31, 7.41-7.45, 7.64-7.70, 7.93, 8.29.

Examples 18-1 to 18-2

A similar procedure to Reference Example 1→Reference Example 2→ReferenceExample 3→Reference Example 4→Reference Example 5→Reference Example6→Reference Example 7→Reference Example 8→Reference Example 9→Example2→Example 15 was carried out by using a corresponding amine compoundinstead of 1,3-dimethylpyrazol-4-amine hydrochloride, using2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine instead of4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine, and using1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl-4-boronic acid instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give thecompound of the present invention having the following physicalproperties.

Example 18-1:(4-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-2,5-difluorophenyl)aceticacid

TLC: Rf 0.41 (ethyl acetate:methanol=20:1);

¹H-NMR (CD₃ OD): δ1.57-1.63, 3.51, 4.95-5.03, 7.04-7.14, 7.17-7.22,7.43-7.54, 8.04, 8.53-8.60.

Example 18-2:2-(4-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-2,3-difluorophenyl)-2-methylpropanoicacid

TLC: Rf 0.61 (ethyl acetate:methanol=20:1);

¹H-NMR (CD3 OD): δ1.54-1.60, 4.94-5.03, 7.07-7.21, 7.43-7.54, 8.03,8.33-8.40.

Reference Example 16: Benzyl[4-({4-amino-7-(propan-2-yl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)-3-methyl-1H-pyrazol-1-yl]acetate

A similar procedure to Reference Example 1→Reference Example 2→ReferenceExample 3→Reference Example 4→Reference Example 5→Reference Example6→Reference Example 7→Reference Example 8→Reference Example 9 wascarried out by using benzyl(4-amino-3-methyl-1H-pyrazol-1-yl)acetateinstead of 1,3-dimethylpyrazol-4-amine hydrochloride, using2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine instead of4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine, and using1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl-4-boronic acid instead of1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid to give the titlecompound having the following physical properties.

TLC: Rf 0.62 (ethyl acetate);

¹H-NMR (CDCl₃): δ1.42-1.58, 1.62-1.84, 2.04-2.23, 2.35, 2.54-2.67,3.73-3.83, 4.03-4.11, 4.80-5.00, 5.22, 5.74-5.80, 6.22, 6.95, 7.19-7.38,7.42-7.49, 7.52-7.57, 8.07.

Reference Example 17:[4-({4-Amino-7-(propan-2-yl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)-3-methyl-1H-pyrazol-1-yl]aceticacid

To a solution of the compound (20 mg) prepared in Reference Example 16in ethanol (1 mL), 10% palladium on carbon (Pd/C) (4 mg) was added, andthe mixture was stirred under a hydrogen gas atmosphere at roomtemperature for 3 hours. The reaction solution was filtered throughCelite, and the filtrate was concentrated under a reduced pressure togive the compound of the present invention (15 mg) having the followingphysical properties.

TLC: Rf 0.39 (ethyl acetate:methanol=1:1);

¹H-NMR (CDCl₃): δ1.42-1.58, 1.62-1.84, 2.00-2.65, 2.35, 3.68-3.83,4.02-4.10, 4.78-4.95, 5.75-5.82, 6.98, 7.13-7.19, 7.42-7.48, 7.59-7.64,7.71, 8.01.

Reference Example 18:2-[4-({4-Amino-7-(propan-2-yl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)-3-methyl-1H-pyrazol-1-yl]acetamide

To a solution of the compound (50 mg) prepared in Reference Example 17in N,N-dimethylformamide (1 mL), diisopropylethylamine (25 μL), ammoniumchloride (8 mg), and2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (hereinafter, abbreviated as HATU) (54 mg) wereadded at room temperature, and the mixture was stirred for 1 hour. Thereaction solution was diluted with ethyl acetate, and was washed withwater, and a saturated saline solution. The obtained organic layer wasdried over anhydrous sodium sulfate, and was concentrated under areduced pressure. The residue was purified by silica gel columnchromatography to give the title compound (37 mg) having the followingphysical properties.

TLC: Rf 0.43 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ1.51-1.59, 1.62-1.88, 2.06-2.24, 2.37, 2.54-2.67,3.73-3.83, 4.03-4.11, 4.77, 4.87-5.01, 5.39-5.62, 5.75-5.80, 6.30, 6.99,7.18-7.21, 7.43-7.49, 7.56-7.61, 8.03, 8.09.

Example 19:2-(4-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methyl-1H-pyrazol-1-yl)acetamide

To a solution of the compound (10 mg) prepared in Reference Example 18in dichloromethane (1 mL), trifluoroacetic acid (140 ILL) was added atroom temperature, and the mixture was stirred for 6 hours. The reactionsolution was diluted with dichloromethane, and was washed with asaturated sodium bicarbonate aqueous solution, and a saturated salinesolution. The obtained organic layer was dried over anhydrous sodiumsulfate, and was concentrated under a reduced pressure. The residue waspurified by preparative thin-layer silica gel column chromatography togive the compound of the present invention (5.5 mg) having the followingphysical properties.

TLC: Rf 0.40 (ethyl acetate:methanol=1:1);

¹H-NMR (CD₃ OD): δ1.56-1.61, 2.29, 4.81, 4.95-5.04, 7.17, 7.19-7.22,7.43-7.57, 8.05, 8.10.

Example 20:(4-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methyl-1H-pyrazol-1-yl)acetonitrile

To a solution of the compound (20 mg) prepared in Reference Example 18in dichloromethane (1.5 mL), pyridine (0.5 mL) and trifluoroaceticanhydride (27 μL) were added at 0° C., and the mixture was stirred atroom temperature for 18 hours. To the reaction solution, a saturatedsodium bicarbonate aqueous solution was added, and the solution wasstirred at room temperature for 16 hours. The reaction solution wasdiluted with dichloromethane, and was washed with a saturated sodiumbicarbonate aqueous solution and a saturated saline solution. Theobtained organic layer was dried over anhydrous sodium sulfate, and wasconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography to give a tetrahydropyran protectedproduct of the title compound (15 mg). A similar procedure to Example 2was carried out by using the tetrahydropyran protected product (15 mg)to give the compound of the present invention having the followingphysical properties.

TLC: Rf 0.29 (ethyl acetate);

¹H-NMR (CDCl₃): δ1.56-1.61, 2.29, 4.88-5.04, 6.41, 7.02, 7.20-7.23,7.43-7.48, 8.14, 8.22.

Example 21:4-{[4-Amino-5-(l-benzofuran-5-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-N-[2-(dimethylamino)ethyl]-3-fluorobenzamide

To a solution of the compound (20 mg) prepared in Example 15 inN,N-dimethylformamide (4 mL), diisopropylethylamine (23 μL),N,N-dimethylethylenediamine (10 μL), and HATU (26 mg) were added at roomtemperature, and the mixture was stirred for 16 hours. The reactionsolution was diluted with ethyl acetate, and was washed with water and,a saturated saline solution. The obtained organic layer was dried overanhydrous sodium sulfate, and was concentrated under a reduced pressure.The residue was purified by silica gel column chromatography to give thecompound of the present invention (19 mg) having the following physicalproperties.

TLC: Rf 0.30 (hexane:ethyl acetate=1:2, NH silica);

¹H-NMR (CDCl₃): δ1.53-1.60, 2.29, 2.49-2.57, 3.48-3.56, 4.94-5.08,6.75-6.83, 6.88, 7.18-7.22, 7.40-7.45, 7.55-7.64, 7.68-7.72, 8.81-8.88.

Example 22:4-{[4-Amino-5-(4-chloro-3-hydroxyphenyl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-fluoro-N-methylbenzamide

To a solution of the compound (32 mg) prepared in Example 14-13 indichloromethane (2 mL), boron tribromide (38 μL) was added at 0° C., andthe mixture was stirred at room temperature for 1 hour. The reactionsolution was cooled to 0° C., and thereafter, ammonia water was added tothe solution. The reaction solution was extracted with dichloromethane,and thereafter, the organic layer was concentrated under a reducedpressure. The residue was purified by preparative HPLC to give atrifluoroacetate of the compound of the present invention. To thetrifluoroacetate, a saturated sodium bicarbonate aqueous solution wasadded, and the mixture was extracted with dichloromethane. The obtainedorganic layer was concentrated under a reduced pressure to give thecompound of the present invention (8 mg) having the following physicalproperties.

TLC: Rf 0.24 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ1.42-1.47, 2.76-2.80, 4.76-4.86, 6.91-6.97,6.98-7.00, 7.17-7.22, 7.63-7.72, 8.36-8.41, 8.43-8.52, 10.28.

Reference Example 19:2,4-Dichloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

A similar procedure to Reference Example 2→Reference Example 4 wascarried out by using 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine instead of4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine, and using oxetan-3-ol insteadof isopropanol to give the title compound having the following physicalproperties.

TLC: Rf 0.51 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ4.84-4.92, 5.15-5.23, 5.92-6.02, 7.89.

Reference Example 20:2-Chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A solution of the compound (127 mg) prepared in Reference Example 19 inammonia/methanol (1.5 mL, 8 M) was stirred in a sealed tube at 90° C.for 16 hours. The reaction solution was diluted with ethyl acetate, andthereafter, was washed with water, and a saturated saline solution. Theobtained organic layer was dried over anhydrous magnesium sulfate, andwas concentrated under a reduced pressure. The residue was washed withwater, hexane, and ethyl acetate to give the title compound (88 mg)having the following physical properties.

TLC: Rf 0.33 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ4.80-4.88, 5.09-5.20, 5.70-5.98, 7.56.

Example 23:1-(4-{[4-Amino-5-(1H-indazol-4-yl)-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methyl-1H-pyrazol-1-yl)-2-methyl-2-propanol

A similar procedure to Reference Example 1→Reference Example 6→ReferenceExample 7→Reference Example 8→Reference Example 9→Example 2 was carriedout by using the compound prepared in Reference Example 20 instead ofthe compound prepared in Reference Example 8, using1-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol instead of1,3-dimethylpyrazol-4-amine hydrochloride, and using[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]boronic acid instead ofthe boronic acid prepared in Reference Example 11 to give the compoundof the present invention having the following physical properties.

TLC: Rf 0.51 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ1.19, 2.29, 4.01, 4.84-4.96, 5.12-5.18, 5.34-5.40,5.65-5.77, 6.33, 7.12, 7.20-7.23, 7.45-7.50, 8.12, 8.23.

Reference Example21:2,4-Dichloro-7-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (188 mg) was dissolved in anaqueous solution (2.7 mL) of potassium hydroxide (898 mg). To thesolution, a solution of 1-chloro-4-chlorodifluoromethanesulfonylbenzene(392 mg) in acetonitrile (3 mL) was added at −78° C., and the mixturewas stirred at 80° C. for 1 hour. To the reaction solution, 1 Nhydrochloric acid was added, the mixture was extracted with ethylacetate, and the organic layer was washed with a saturated salinesolution. The obtained organic layer was dried over anhydrous sodiumsulfate, and thereafter, was concentrated under a reduced pressure. Theresidue was washed with methanol, and thereafter, was filtrated to givethe title compound (96 mg) having the following physical properties.

TLC: Rf 0.25 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ6.78-6.80, 7.52-7.92.

Example 24:4-{[4-Amino-5-(1-benzofuran-5-yl)-7-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-fluoro-N,N-dimethylbenzamide

A similar procedure to Reference Example 1→Reference Example 2→ReferenceExample 3→Reference Example 5→Reference Example 6→Reference Example7→Reference Example 8→Reference Example 9 was carried out by using thecompound prepared in Reference Example 21 instead of4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine, using benzofuran-5-boronicacid instead of 1-(tert-butyldimethylsilyl)-1H-indol-5-ylboronic acid,and using 4-amino-3-fluoro-N,N-dimethylbenzamide instead of2-fluoro-4-(methylsulfonyl)aniline to give the compound of the presentinvention having the following physical properties.

TLC: Rf 0.37 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ3.00-3.18, 5.02-5.12, 6.82-6.84, 7.05, 7.16-7.19,7.21-7.27, 7.40-7.45, 7.48-7.89, 8.58-8.64.

Reference Example 22: N,N-dibenzyl-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (19 mg) inisopropanol (1 mL), dibenzylamine (20 mg) was added, and the mixture wasstirred at room temperature for 2 hours. The reaction solution wasconcentrated under a reduced pressure, and thereafter, the residue waspurified by silica gel column chromatography to give the title compound(30 mg) having the following physical properties.

¹H-NMR (CDCl₃): δ4.99, 6.49-6.53, 7.28-7.36, 7.55-7.59.

Reference Example 23:4-{[4-(Dibenzylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl]amino}-3-fluoro-N,N-dimethylbenzamide

To a solution of the compound (30 mg) prepared in Reference Example 22and 4-amino-3-fluoro-N,N-dimethylbenzamide (31.5 mg) in tert-butanol (2mL), potassium carbonate (36 mg) and Xantphos (10 mg) were added, andthe mixture was deaerated. Under a nitrogen atmosphere, to the reactionsolution, tris(dibenzylideneacetone)dipalladium(0)(Pd₂ (dba)₃) (8 mg)was added, and the mixture was heated at 120° C. for 1 hour by using amicrowave. The reaction solution was diluted with ethyl acetate, and waswashed with water, and a saturated saline solution. The obtained organiclayer was dried over anhydrous sodium sulfate, and was concentratedunder a reduced pressure. The residue was purified by silica gel columnchromatography to give the title compound (40 mg) having the followingphysical properties.

¹H-NMR (CDCl₃): 53.06, 5.01, 6.42-6.49, 6.73, 7.15, 7.20, 7.28-7.38,7.50-7.51, 8.50.

Reference Example 24:4-{[7-Bromo-4-(dibenzylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl]amino}-3-fluoro-N,N-dimethylbenzamide

To a solution of the compound (30 mg) prepared in Reference Example 23in dichloromethane (5 mL), N-bromosuccinimide (11 mg) was added at 0°C., and the mixture was stirred for 15 minutes. The reaction solutionwas diluted with dichloromethane, and was washed with water, and asaturated saline solution. The obtained organic layer was dried overanhydrous sodium sulfate, and was concentrated under a reduced pressure.The residue was purified by silica gel column chromatography to give thetitle compound (40 mg) having the following physical properties.

¹H-NMR (CDCl₃): δ3.07, 4.99, 6.52, 6.85, 6.87, 7.19-7.23, 7.27-7.38,8.68.

Reference Example 25:4-{[4-(Dibenzylamino)-7-(prop-1l-en-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl]amino}-3-fluoro-N,N-dimethylbenzamide

To a solution of the compound (40 mg) prepared in Reference Example 24in N,N-dimethylformamide (3 mL),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (24 mg), 2 Msodium bicarbonate aqueous solution (0.11 mL), and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex (PdCl₂ (dppf).CH₂ Cl₂ complex) (6 mg)were added. The reaction solution was deaerated, and thereafter, under anitrogen atmosphere, the solution was stirred at 80° C. for 2 hours. Thereaction solution was diluted with ethyl acetate, and was washed withwater, and a saturated saline solution. The obtained organic layer wasdried over anhydrous sodium sulfate, and was concentrated under areduced pressure. The residue was purified by silica gel columnchromatography to give the title compound (35 mg) having the followingphysical properties.

¹H-NMR (CDCl₃): δ2.22, 3.06, 5.01, 5.38, 6.21, 6.47, 6.50, 6.75,7.12-7.21, 7.27-7.38, 8.41.

Reference Example 26:4-{[4-Amino-7-(propan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl]amino}-3-fluoro-N,N-dimethylbenzamide

To a solution of the compound (35 mg) prepared in Reference Example 25in ethanol (3 mL), palladium hydroxide on carbon (Pd(OH)₂/C) (3.5 mg, 10wt %) was added, and under a hydrogen gas atmosphere, the mixture wasstirred at 80° C. for 16 hours. The reaction solution was filteredthrough Celite, and thereafter, the filtrate was concentrated under areduced pressure. The residue was purified by silica gel columnchromatography to give the title compound (15 mg) having the followingphysical properties.

¹H-NMR (CDCl₃): δ1.34, 3.08, 3.46-3.53, 5.20, 6.38, 6.55, 6.80,7.20-7.29, 8.61.

Reference Example 27:4-{[4-Amino-5-bromo-7-(propan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl]amino}-3-fluoro-N,N-dimethylbenzamide

To a solution of the compound (100 mg) prepared in Reference Example 26in tetrahydrofuran (30 mL), N-bromosuccinimide (50 mg) was added at −78°C., and the mixture was stirred for 15 minutes. The reaction solutionwas diluted with dichloromethane, and was washed with water, and asaturated saline solution. The obtained organic layer was dried overanhydrous sodium sulfate, and was concentrated under a reduced pressure.The residue was purified by silica gel column chromatography to give thetitle compound (130 mg) having the following physical properties.

¹H-NMR (CDCl₃): δ1.34, 3.08, 3.40-3.47, 6.19, 6.36, 6.96, 7.21-7.27,8.48.

Reference Example 28:4-({4-Amino-5-[3-(benzyloxy)phenyl]-7-(propan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl}amino)-3-fluoro-N,N-dimethylbenzamide

To a solution of the compound (130 mg) prepared in Reference Example 27in 1,4-dioxane (15 mL), 3-benzyloxyphenylboronic acid (137 mg), 2 Mtripotassium phosphatean aqueous solution (0.45 mL), andtetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄) (69 mg) were added.The reaction solution was deaerated, and thereafter, under a nitrogenatmosphere, the solution was stirred at 100° C. for 16 hours. Thereaction solution was diluted with ethyl acetate, and was washed withwater, and a saturated saline solution. The obtained organic layer wasdried over anhydrous sodium sulfate, and was concentrated under areduced pressure. The residue was purified by silica gel columnchromatography to give the title compound (33 mg) having the followingphysical properties.

¹H-NMR (CDCl₃): δ1.42, 3.09, 3.48-3.55, 5.13, 6.37, 6.78, 6.97-7.00,7.07-7.09, 7.21-7.24, 7.28-7.29, 7.34-7.46, 8.61.

Example 25:4-{[4-Amino-5-(3-hydroxyphenyl)-7-isopropylpyrrolo[2,1-f][1,2,4]triazin-2-yl]amino}-3-fluoro-N,N-dimethylbenzamide

To a solution of the compound (33 mg) prepared in Reference Example 28in ethanol (10 mL), palladium hydroxide on carbon (Pd(OH)₂/C) (6.6 mg,20 wt %) was added, and under a hydrogen gas atmosphere, the mixture wasstirred at room temperature for 2 hours. The reaction solution wasfiltered through Celite, and thereafter, the filtrate was concentratedunder a reduced pressure. The residue was purified by reverse-phasecolumn chromatography (C18, 10-90% acetonitrile/water, Isco CombiflashCompanion MPLC system) to give the compound of the present invention (17mg) having the following physical properties.

¹H-NMR (CDCl₃): δ1.41, 3.09, 3.47-3.54, 5.27, 5.95, 6.34, 6.73-6.88,6.99-7.02, 7.19-7.25, 8.61.

Purity (LC-MS/ELSD): 100% (Retention time: 0.96 minutes);

MASS (ESI, Pos.): 449 (M+H)*.

Examples 26-1 to 26-3

A similar procedure to Reference Example 23→Reference Example24→Reference Example 25→Reference Example 26→Reference Example27→Reference Example 28→Example 2 was carried out by using4-amino-3-fluoro-N,N-dimethylbenzamide or a corresponding amine compoundinstead of 4-amino-3-fluoro-N,N-dimethylbenzamide, and using1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazoleinstead of 4-benzyloxyphenylboronic acid to give the compound of thepresent invention having the following physical properties. Meanwhile,HPLC preparative purification was performed instead of silica gel columnchromatography in Example 2.

Example 26-1:4-{[4-Amino-5-(1H-indazol-4-yl)-7-isopropylpyrrolo[2,1-f][1,2,4]triazin-2-yl]amino}-3-fluoro-N,N-dimethylbenzamidetrifluoroacetate

¹H-NMR (CDCl₃): δ1.35, 2.98, 3.36-3.45, 6.55, 7.13-7.55, 7.97, 8.07,8.61, 13.21.

Purity (LC-MS/ELSD): 100% (Retention time: 0.94 minutes);

MASS (ESI, Pos.): 473 (M+H)⁺.

Example 26-2:N²-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(1H-indazol-4-yl)-7-isopropylpyrrolo[2,1-f][1,2,4]triazine-2,4-diaminetrifluoroacetate

¹H-NMR (DMSO-d₆): δ1.38, 3.23, 3.41-3.51, 6.59, 7.23, 7.41-7.56,7.71-7.77, 7.98, 8.46, 8.55.

Purity (LC-MS/ELSD): 100%/(Retention time: 0.97 minutes);

MASS (ESI, Pos.): 480 (M+H)⁺.

Example 26-3:N²-(1,3-dimethyl-1H-pyrazol-4-yl)-5-(1H-indazol-4-yl)-7-isopropylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine trifluoroacetate

¹H-NMR (DMSO-d₆): δ1.36, 2.15, 3.38-3.45, 3.75, 6.50, 7.10-7.12,7.40-7.44, 7.52-7.54, 7.84-7.97, 7.98, 13.21.

Purity (LC-MS/ELSD): 99.8% (Retention time: 0.81 minutes);

MASS (ESI, Pos.): 402 (M+H)⁺.

Pharmacological Experimental Examples Pharmacological ExperimentalExample 1: Measurement of Brk Inhibitory Activity

Measurement of an inhibitory activity on Brk enzyme was performed byusing LanthaScreen (registered trademark) system (Invitrogen) inaccordance with the attached manual. Reagents used are described below.

Reaction Buffer: A solution containing 50 mmol/L HEPES (pH 7.5), 0.01%Brij 35, 10 mmol/L MgCl₂ and 1 mmol/L EGTA was prepared by usingpurified water.

A solution of a test substance (the compound of the present invention):A solution of each concentration of a test compound in DMSO was diluted20-fold with Reaction Buffer, and a solution containing a test compoundat a concentration 5 times a final concentration was prepared.

An enzyme solution: A solution containing 480 ng/mL of Brk enzyme wasprepared by using Reaction Buffer.

A substrate solution: A solution containing 57 μmol/L of ATP and 500nmol/L of Fluorescein-Poly GT (Invitrogen) was prepared by usingReaction Buffer.

A detection solution: A solution containing 20 mmol/L of EDTA and 4nmol/L of PY20 (Invitrogen) was prepared by using Dilution B(Invitrogen).

To a 96-well plate (Nunc), a solution of 10 mmol/L of a test compound inDMSO was dispensed, and further, a dilution series at a common ratio ofthree was prepared by using DMSO. To each of wells of the 96-well platefor the measurement, 5 μL of Reaction Buffer containing DMSO was addedfor a blank group and a vehicle group and 5 μL of a test substancesolution was added for a test substance group. Next, 10 μL per well ofReaction Buffer was added for the blank group, and 10 μL per well of theenzyme solution was added for the vehicle group and the test compoundgroup, and thereafter, the mixture was stirred at room temperature for10 minutes. After completion of stirring, 10 μL of the substratesolution was added to each of wells, and the mixture was stirred at roomtemperature under a shading condition for 1 hour. After completion ofthe reaction, 25 μL of the detection solution was added to each well,and the mixture was left to stand at room temperature under a shadingcondition for 30 minutes. After being left standing, fluorescenceintensities at 520 nm and 495 nm were measured by using Analyst GT(Molecular Devices, LLC) when being irradiated with an excitation lightat 340 nm. The phosphorylation of the artificial substrate wasquantified by Tune-Resolved Fluorescence Resonance Energy Transfer(TR-FRET). With regard to each well, the TR-FRET ratio was calculated bydivining the fluorescence signal at 520 nm by the fluorescence signal at495 nm, and the inhibition rate (%) in the test compound group wascalculated according to the following Numerical Formula 1.Inhibition rate (%)={1−(TR-FRET ratio of test compoundgroup−A)(B−A)}×100  [Numerical Formula 1]

A: Mean value of TR-FRET ratio of blank group

B: Mean value of TR-FRET ratio of vehicle group

The value (IC₅ ₀ value) of 50% inhibition rate of the test compound wascalculated from the inhibition curve based on the inhibition rate ateach concentration of the test compound.

As a result, it was found that each IC₅ ₀ value of the compounds of thepresent invention was equal to or lower than 0.1 μmol/L, and thecompound of the present invention has a potent Brk inhibitory activity.For example, IC₅ ₀ values of several compounds of the present inventionwere as shown in the following Table 1.

TABLE 1 Example No. Brk inhibitory activity (IC₅₀, nM)  1 2.1  2 5.4 4-1 5.1  4-2 9.3  4-3 8.5  8 7.6 10 6.9 12 5.1 13-1 3.3 13-9 4.1 14-412  14-11 50 18-1 7.7 23 9.7 25 3.4 26-1 3.7

Pharmacological Experimental Example 2: Tests of Enzyme InhibitoryActivities on Kinases Other than Brk (Experiment on Selectivity)

2-1: Lck Inhibitory Activity

Tyrosine phosphorylation of Lck was performed by using Z'-LYTE KinaseAssay Kit-Tyr 2 Peptide (Invitrogen) containing the following reagents(Tyr 2 Peptide, Tyr 2 Phospho-Peptide, 5× Kinase Buffer, ATP, ColoringReagent A, Coloring Buffer, and Stop Reagent) and Lck. The Lck activitywas determined by using Fluorescence Resonance Energy Transfer (FRET)method.

A dilute solution (5 μL) of the compound of the present invention indimethylsulfoxide (DMSO; Sigma-Aldrich Co. LLC) was added to a 96-wellassay plate. In addition, Peptide/Kinase Buffer composed ofDL-dithiothreitol (DTT; 2 mM), Tyr 2 Peptide (2 μM), Kinase Buffer andLck was added to the assay plate, and the reaction solution waspreincubated at 25° C. for 20 minutes. Then, ATP solution (5 μL)composed of adenosine triphosphate (ATP; 45 μM) and Kinase Buffer wasadded, and the reaction solution was incubated at 25° C. for 1 hour.After incubation, Coloring Solution A (10 μL) composed of ColoringReagent B and Coloring Buffer was added, and the reaction solution wasincubated at 25° C. for 1 hour. Stop Reagent (10 μL) was added to eachwell such that the enzymatic reaction stopped. The fluorescent coloringof each well was measured on a fluorescent plate reader by usingwavelengths of 445 nm and 520 nm. The ratio of phosphorylation wasdetermined by a ratio of coloring at 445 nm to that at 520 nm accordingto the attached manual.

The inhibition rate (%) of the compound of the present invention wascalculated according to the following Numerical Formula 2.Inhibition rate (%)={1−(AX−AB)/(AC−AB)}×100  [Numerical Formula 2]

AX: Ratio of phosphorylation at addition of the compound of the presentinvention

AB: Ratio of phosphorylation in blank

AC: Ratio of phosphorylation at addition of only DMSO

The value of 50% inhibition rate (IC₅ ₀) of the compound of the presentinvention was determined from the inhibition curve based on theinhibition rate at each concentration of the compound of the presentinvention.

2-2: Syk Inhibitory Activity

The compound of the present invention was dissolved in DMSO to prepare asolution with a concentration of 100 times the test concentration of 1μmol/L. The solution was further diluted 25-fold with Assay Buffer (20mmol/L HEPES, 0.01% Triton X-100, 2 mmol/L DTT, pH 7.5) to give a testsubstance solution. With regard to a positive control substance(Staurosporine), a solution of the positive control substance wasprepared in a similar manner.

Five microliters of a test substance solution with a concentration offour times prepared by using Assay Buffer, 5 μL of a solution of asubstrate (Blk/Lyntide)/ATP/a metal (Mg) with a concentration of fourtimes and 10 μL of a solution of Syk kinase with a concentration of twotimes were mixed in a well of a 384-well plate made of polypropylene,and the mixture was subjected to a reaction at room temperature for 1hour (the final concentration of the substrate was 1,000 nmol/L, and thefinal concentration of ATP was 26 μmol/L). To the mixture, 60 μL ofTermination Buffer (QuickScout Screening Assist MSA; Carna Biosciences,Inc.) was added to stop the reaction. The substrate peptide and thephosphorylated peptide in the reaction solution were separated, and werequantified. The kinase reaction was evaluated by a product ratio(P/(P+S)) calculated from a peak height (S) of the substrate peptide anda peak height (P) of the phosphorylated peptide.

The inhibition rates of the compounds of the present invention on Lckand Syk kinases in Pharmacological Example 2, for example, in the casesof the compounds of the present invention of Example 1, Example 4-3, andExample 13-1, were as shown in the following Table 2.

TABLE 2 Lck inhibitory activity Syk inhibitory activity Example No.(IC₅₀, μM) (Inhibition rate at 1 μM of compound) 1 >10 0%  4-3 2.5 0%13-1 >10 0%

From the result, with regard to a selective inhibitory activity on Brkto Lck, in the case of the compound of Example 1, the selectiveinhibitory activity on Brk to Lck was 4,762-fold, in the case of thecompound of Example 4-3, the selective inhibitory activity on Brk to Lckwas 294-fold, and in the case of the compound of Example 13-1, theselective inhibitory activity on Brk to Lck was 3,030-fold. In addition,on Syk, each of three compounds had no inhibitory activity at 1 μM.Accordingly, it was found that the compound of the present invention hasa potent Brk inhibitory activity and is excellent in Brk selectivity.

Preparation Examples Preparation Example 1

The following ingredients can be mixed in a conventional manner andcompressed to give 10,000 tablets each containing 10 mg of the activeingredient.

N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine. . . 100 g

Carboxymethyl cellulose calcium (a disintegrating agent) . . . 20 g

Magnesium stearate (a lubricant) . . . 10 g

Microcrystalline cellulose . . . 870 g

INDUSTRIAL APPLICABILITY

The compound of the present invention has a Brk inhibitory activity, andis effective for the prevention and/or treatment of diseases in whichBrk involves, for example, cancer and the like.

The invention claimed is: 1.N⁶-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(1H-indol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;a salt thereof, a solvate thereof, or an N-oxide thereof.
 2. A compoundrepresented by structural formula as below,


3. A salt of a compound represented by structural formula as below,